{ "$schema_version": "5.3", "review_mode": "revision", "claim_restatement": { "index_wording": "Enhancer–Promoter Looping as Causal", "entry_form": "claim", "gradeable_restatement": "Physical enhancer-promoter looping is required to initiate and maintain transcriptional bursting rather than being a correlate of activity.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Endogenous versus ectopic locus, tissue, activation history, contact assay, spatial/temporal resolution and initiation versus maintenance", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Enhancer–Promoter Looping as Causal", "central_claim": "Physical enhancer-promoter looping is required to initiate and maintain transcriptional bursting rather than being a correlate of activity.", "proposed_mechanism": "Physical enhancer-promoter looping is required to initiate and maintain transcriptional bursting rather than being a correlate of activity.", "claimed_scope": "Mammalian endogenous enhancers and promoters, activation history and cell state fixed; continuous molecular contact during initiation and maintenance tested separately from engineered proximity.", "claimed_level": [ "initiation", "maintenance" ], "is_conjunctive": true, "conjunctive_note": "The exact index states primary-subclaim aggregation; SC3 is the continuous-contact necessity gate, with engineered sufficiency and graded-probability effects reported separately. The prior private edition is preserved and not consulted for its score until a source checkpoint." }, "rubric_routing": { "primary_rubric": "03-epigenetics-gene-regulation.md", "secondary_rubrics": [], "index_notes_applied": [ "The exact index states primary-subclaim aggregation; SC3 is the continuous-contact necessity gate, with engineered sufficiency and graded-probability effects reported separately. The prior private edition is preserved and not consulted for its score until a source checkpoint." ], "rubric_fit_note": "Rubric03 fits endogenous transcriptional output; no disease/clinical extrapolation. Exact index SC3 falsification and SC2 synthetic-tether cap are applied." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Enhancers and promoters are spatially closer than random loci reproducibly.", "subclaim_type": "existence", "scope": "Locus, assay and cell state specified before observation", "claimed_scope": "Locus, assay and cell state specified before observation", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Contact mapping and live imaging", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Orthogonal regulatory contact maps and native imaging establish enrichment and spatial organization, with locus/state exceptions. Association establishes the observation without causal transfer; Β is retained." }, { "id": "SC2", "statement": "Engineered proximity can activate a silenced endogenous promoter.", "subclaim_type": "sufficiency", "scope": "Synthetic tethering distinguished from endogenous necessity", "claimed_scope": "Synthetic tethering distinguished from endogenous necessity", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Forced proximity with functional transcriptional outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "LDB1 tethering activates selected silent native globin promoters with enhancer-deletion and targeting controls. This is causal engineered intervention, but the exact index states synthetic-tether sufficiency is governed by the non-endogenous cap; Γ limits its inference to natural looping. Loop-competent activation-defective rescue also proves geometry alone is not sufficient." }, { "id": "SC3", "statement": "Continuous enhancer-promoter contact is necessary to initiate and maintain transcriptional bursting.", "subclaim_type": "necessity", "scope": "Endogenous locus, spatial resolution and temporal sampling stated", "claimed_scope": "Endogenous locus, spatial resolution and temporal sampling stated", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Acute contact disruption with viability controls and simultaneous live transcription", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "No positive selective release/rescue test establishes uninterrupted native contact through both initiation and maintenance. The exact index mandates a falsification pattern for contrary endogenous predictions. Apply one downgrade from mechanistic Γ to Β, retaining reporter delay, label offset and unresolved ultrabrief encounters rather than asserting zero contacts." }, { "id": "SC4", "statement": "Contact probability modulates transcriptional burst frequency.", "subclaim_type": "mechanism", "scope": "Distance/context predefined; no inference of continuous contact from population average", "claimed_scope": "Distance/context predefined; no inference of continuous contact from population average", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Endogenous distance/architecture perturbation and bursting", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Forced native-globin tethers alter snapshot burst fraction and ectopic graded landscapes fit promoter on-rate modulation. Neither measures selectively varied native contact probability with direct live burst frequency; active tether chemistry, distance changes and synthetic context remain. The broad registered claim retains Γ, with causal engineered output acknowledged separately." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "The exact index states primary-subclaim aggregation; SC3 is the continuous-contact necessity gate, with engineered sufficiency and graded-probability effects reported separately. The prior private edition is preserved and not consulted for its score until a source checkpoint.", "primary_subclaim_id": "SC3", "aggregation_derivation": "The registered primary SC3 necessity gate is Β: partial mechanistic plausibility is capped at Γ, then one endogenous-prediction falsification pattern lowers it one rung. Native Sox2 simultaneous imaging and orthogonal neural Shh/estrogen distance findings oppose the universal sustained-contact prediction within detection limits. This is neither proof that brief contacts never occur nor a denial of causal enhancer function. Exact index additionally restricts synthetic SC2 sufficiency to Γ; broad SC4 graded frequency remains Γ because its strongest controlled tests use synthetic tethers/landscapes and snapshot or inferred kinetics.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Β", "scope_matched_would_return": "Β", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Topological corral and context-specific architecture", "core_claim": "Architecture and local environments reinforce selected long-range regulation without a persistent contact switch.", "explains_what_nominal_does_not": "Architecture and local environments reinforce selected long-range regulation without a persistent contact switch.", "strongest_supporting_evidence": [ "Native Shh topology alleles show redundancy and enhancer-dependent robustness; contact maps distinguish microcompartments from extrusion loops." ], "strongest_contradictory_evidence": [ "Microcompartment presence itself is association; not all loci require the same architecture." ], "hsef_level_for_this_model": "Ε", "rationale": "Native Shh topology alleles show redundancy and enhancer-dependent robustness; contact maps distinguish microcompartments from extrusion loops. Microcompartment presence itself is association; not all loci require the same architecture." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Cohesin biochemical coupling and pause regulation", "core_claim": "Cohesin changes regulatory-factor delivery, recruitment and pausing beyond average DNA proximity.", "explains_what_nominal_does_not": "Cohesin changes regulatory-factor delivery, recruitment and pausing beyond average DNA proximity.", "strongest_supporting_evidence": [ "Quiescent macrophage conditional deletion alters burst participation while measured distances remain similar; CTCF domain separation and human kinetic studies distinguish protein functions." ], "strongest_contradictory_evidence": [ "A unified pause-release mechanism is not established across all loci; multifunctional protein loss is not contact-selective." ], "hsef_level_for_this_model": "Ε", "rationale": "Quiescent macrophage conditional deletion alters burst participation while measured distances remain similar; CTCF domain separation and human kinetic studies distinguish protein functions. A unified pause-release mechanism is not established across all loci; multifunctional protein loss is not contact-selective." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Contact-probability modulation", "core_claim": "Encounters affect entry into active promoter states with transcriptional memory after contact ends.", "explains_what_nominal_does_not": "Encounters affect entry into active promoter states with transcriptional memory after contact ends.", "strongest_supporting_evidence": [ "Functional globin tethers and graded synthetic landscapes support burst-participation or on-rate effects." ], "strongest_contradictory_evidence": [ "Native burst frequency and contact probability must be varied separately from tether chemistry, enhancer strength and genomic distance." ], "hsef_level_for_this_model": "Γ", "rationale": "Functional globin tethers and graded synthetic landscapes support burst-participation or on-rate effects. Native burst frequency and contact probability must be varied separately from tether chemistry, enhancer strength and genomic distance." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Transcription-factor activity gradient", "core_claim": "Mobile regulatory factors mediate nearby enhancer-promoter influence without sustained DNA contact.", "explains_what_nominal_does_not": "Mobile regulatory factors mediate nearby enhancer-promoter influence without sustained DNA contact.", "strongest_supporting_evidence": [ "Nanoenvironment measurements, condensate-distance effects and purified reconstitution establish feasible local-factor routes." ], "strongest_contradictory_evidence": [ "Direct endogenous gradient-specific loss/rescue is not isolated; a useful explanatory mechanism remains nonunique." ], "hsef_level_for_this_model": "Γ", "rationale": "Nanoenvironment measurements, condensate-distance effects and purified reconstitution establish feasible local-factor routes. Direct endogenous gradient-specific loss/rescue is not isolated; a useful explanatory mechanism remains nonunique." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Continuous physical contact necessary", "core_claim": "Uninterrupted enhancer-promoter contact is required during burst initiation and maintenance.", "explains_what_nominal_does_not": "Uninterrupted enhancer-promoter contact is required during burst initiation and maintenance.", "strongest_supporting_evidence": [ "Contact enrichment and active tether effects motivate this strong model." ], "strongest_contradictory_evidence": [ "Native measured proximity is uncoupled from bursts and activation can increase separation; one index-directed falsification downgrade applies, with brief encounters unresolved." ], "hsef_level_for_this_model": "Β", "rationale": "Contact enrichment and active tether effects motivate this strong model. Native measured proximity is uncoupled from bursts and activation can increase separation; one index-directed falsification downgrade applies, with brief encounters unresolved." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Native Shh topology alleles (PMID31147463, PMID31511252) distinguish context-limited architecture reinforcement from universal persistence; macrophage cohesin coupling (PMID35896525) demonstrates output dependence without large measured distance change. No single experiment identifies one universal rival: these are separate context-scoped mechanisms, not independent confirmations of an omnibus model.", "study_separating_rank1_from_rank2": "Native Shh topology alleles (PMID31147463, PMID31511252) distinguish context-limited architecture reinforcement from universal persistence; macrophage cohesin coupling (PMID35896525) demonstrates output dependence without large measured distance change. No single experiment identifies one universal rival: these are separate context-scoped mechanisms, not independent confirmations of an omnibus model.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "38194964", "title": "Direct observation of a condensate effect on super-enhancer controlled gene bursting.", "citation": "Du M, Stitzinger SH, Spille JH et al. Direct observation of a condensate effect on super-enhancer controlled gene bursting. Cell. 2024.", "doi": "10.1016/j.cell.2023.12.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38194964/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38194964/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38614098" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38194964", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native Sox2 mouse ESC imaging", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Condensate distance predicts burst enhancement better than enhancer distance; basal bursts persist.", "what_it_does_not_show": "Condensate geometry is not direct DNA-contact necessity; linked correction body remains unexamined.", "confounders_present": [ "Condensate geometry is not direct DNA-contact necessity; linked correction body remains unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 2, "pmid": "31124784", "title": "Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity.", "citation": "Alexander JM, Guan J, Li B et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. eLife. 2019.", "doi": "10.7554/eLife.41769", "pmcid": "PMC6534382", "url": "https://pubmed.ncbi.nlm.nih.gov/31124784/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31124784/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31124784", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph20, 1:Results:paragraph42, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native Sox2 live mouse ESC", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Enhancer-dependent native Sox2 bursts show no contemporaneous, tested lag-window or cell-average relation to measured enhancer proximity.", "what_it_does_not_show": "Labels are kilobases from elements, finite resolution and 0.5–2-minute reporter delay leave ultrabrief or earlier contacts possible; imaging null is a prediction challenge, not direct selective contact-ablation proof.", "confounders_present": [ "Labels are kilobases from elements, finite resolution and 0.5–2-minute reporter delay leave ultrabrief or earlier contacts possible; imaging null is a prediction challenge, not direct selective contact-ablation proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 3, "pmid": "27405777", "title": "Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers.", "citation": "Breda L, Motta I, Lourenco S et al. Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood. 2016.", "doi": "10.1182/blood-2016-01-691089", "pmcid": "PMC5000846", "url": "https://pubmed.ncbi.nlm.nih.gov/27405777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27405777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27405777", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "primary human sickle erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Targeted globin looping raises fetal hemoglobin and reduces sickling with low measured toxicity.", "what_it_does_not_show": "Shared LDB1 platform; ex vivo efficacy does not measure continuous same-cell contact.", "confounders_present": [ "Shared LDB1 platform; ex vivo efficacy does not measure continuous same-cell contact." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Related globin tether platform." ] }, { "n": 4, "pmid": "25126789", "title": "Reactivation of developmentally silenced globin genes by forced chromatin looping.", "citation": "Deng W, Rupon JW, Krivega I et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014.", "doi": "10.1016/j.cell.2014.05.050", "pmcid": "PMC4134511", "url": "https://pubmed.ncbi.nlm.nih.gov/25126789/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25126789/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25126789", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse and primary human globin loci", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Tethered LDB1 reactivates silenced globin genes, depends on LCR and redirects promoter contacts.", "what_it_does_not_show": "Tether is a functional protein domain rather than inert geometry; continuous necessity untested.", "confounders_present": [ "Tether is a functional protein domain rather than inert geometry; continuous necessity untested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Related globin tether platform, not independent intervention chemistry." ] }, { "n": 5, "pmid": "36852088", "title": "Forced enhancer-promoter rewiring to alter gene expression in animal models.", "citation": "Peslak SA, Demirci S, Chandra V et al. Forced enhancer-promoter rewiring to alter gene expression in animal models. Molecular therapy. Nucleic acids. 2023.", "doi": "10.1016/j.omtn.2023.01.016", "pmcid": "PMC9958407", "url": "https://pubmed.ncbi.nlm.nih.gov/36852088/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36852088/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36852088", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human globin transgene mice and macaque grafts", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Rewiring raises fetal globin in two transplanted animal settings.", "what_it_does_not_show": "Shared reagent; engineered graft output does not establish universal mammalian promoter mechanism.", "confounders_present": [ "Shared reagent; engineered graft output does not establish universal mammalian promoter mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Related tether transplanted into new species; species difference does not independently validate intervention specificity." ] }, { "n": 6, "pmid": "28520978", "title": "LDB1-mediated enhancer looping can be established independent of mediator and cohesin.", "citation": "Krivega I, Dean A. LDB1-mediated enhancer looping can be established independent of mediator and cohesin. Nucleic acids research. 2017.", "doi": "10.1093/nar/gkx433", "pmcid": "PMC5737898", "url": "https://pubmed.ncbi.nlm.nih.gov/28520978/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28520978/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28520978", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native erythroid locus editing", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "TATA deletion stops transcription while contact remains; activation-deficient LDB1 restores loops without mediator or cohesin.", "what_it_does_not_show": "Disentangles transcription machinery from looping; does not prove all contacts unnecessary.", "confounders_present": [ "Disentangles transcription machinery from looping; does not prove all contacts unnecessary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 7, "pmid": "36471071", "title": "Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1.", "citation": "Hsieh TS, Cattoglio C, Slobodyanyuk E et al. Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1. Nature genetics. 2022.", "doi": "10.1038/s41588-022-01223-8", "pmcid": "PMC9729117", "url": "https://pubmed.ncbi.nlm.nih.gov/36471071/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36471071/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36471071", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph21, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse ESC acute degrons Micro-C and nascent RNA", "decisive_perturbation": true, "endogenous": false, "direction": "null", "what_it_shows": "Most enhancer-promoter contacts and transcription persist after acute extrusion-factor loss; TF binding decreases.", "what_it_does_not_show": "Contacts largely remain, so depletion is not a selective contact-ablation necessity test; short window and thresholds matter.", "confounders_present": [ "Contacts largely remain, so depletion is not a selective contact-ablation necessity test; short window and thresholds matter." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Reuses baseline Micro-C material from 32213323; acute perturbations add new observations." ] }, { "n": 8, "pmid": "41254162", "title": "Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation.", "citation": "Narita T, Kilic S, Higashijima Y et al. Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation. Nature genetics. 2025.", "doi": "10.1038/s41588-025-02404-x", "pmcid": "PMC12695661", "url": "https://pubmed.ncbi.nlm.nih.gov/41254162/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41254162/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID41402458" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41254162", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph23, 1:Results:paragraph25, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse ESC and neural precursor nascent RNA", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "CBP/p300 target stratification detects reproducible subtle cohesin effects; loop-defective CTCF retains promoter activation.", "what_it_does_not_show": "Constitutive mutant adaptation, response thresholds and linked unexamined correction limit detailed attribution.", "confounders_present": [ "Constitutive mutant adaptation, response thresholds and linked unexamined correction limit detailed attribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "38206813", "title": "ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry.", "citation": "Zhang M, Huang H, Li J et al. ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry. Cell reports. 2024.", "doi": "10.1016/j.celrep.2023.113663", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38206813/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38206813/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38206813", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "ZNF143 deletion and CTCF degradation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ZNF143 binds directional sites and affects looping and CTCF/cohesin arrangement.", "what_it_does_not_show": "DNA binding and promoter activity change with geometry; uninterrupted contact requirement is not isolated.", "confounders_present": [ "DNA binding and promoter activity change with geometry; uninterrupted contact requirement is not isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 10, "pmid": "35418676", "title": "Nonlinear control of transcription through enhancer-promoter interactions.", "citation": "Zuin J, Roth G, Zhan Y et al. Nonlinear control of transcription through enhancer-promoter interactions. Nature. 2022.", "doi": "10.1038/s41586-022-04570-y", "pmcid": "PMC9021019", "url": "https://pubmed.ncbi.nlm.nih.gov/35418676/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35418676/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35418676", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 2:Enhancer contacts modulate burst frequency:paragraph0, 2:Enhancer contacts modulate burst frequency:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "hundreds of engineered mouse ESC lines", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Contact probability relates nonlinearly to reporter output and inferred promoter on-rate with alternative-model controls.", "what_it_does_not_show": "Founder-line contact probabilities and simplified ectopic locus do not directly track native contact during individual bursts.", "confounders_present": [ "Founder-line contact probabilities and simplified ectopic locus do not directly track native contact during individual bursts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 11, "pmid": "29053968", "title": "Multiscale 3D Genome Rewiring during Mouse Neural Development.", "citation": "Bonev B, Mendelson Cohen N, Szabo Q et al. Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell. 2017.", "doi": "10.1016/j.cell.2017.09.043", "pmcid": "PMC5651218", "url": "https://pubmed.ncbi.nlm.nih.gov/29053968/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29053968/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29053968", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse neural differentiation maps", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cell-type contacts accompany expression; activation alone does not create TAD boundaries.", "what_it_does_not_show": "Temporal covariation and maps cannot isolate uninterrupted burst contact causality.", "confounders_present": [ "Temporal covariation and maps cannot isolate uninterrupted burst contact causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 12, "pmid": "29224777", "title": "YY1 Is a Structural Regulator of Enhancer-Promoter Loops.", "citation": "Weintraub AS, Li CH, Zamudio AV et al. YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017.", "doi": "10.1016/j.cell.2017.11.008", "pmcid": "PMC5785279", "url": "https://pubmed.ncbi.nlm.nih.gov/29224777/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29224777/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29224777", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "YY1 editing and depletion mammalian cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "YY1 site deletion or depletion alters contacts and expression.", "what_it_does_not_show": "Longer perturbation and direct transcription-factor functions confound geometry; acute Hsieh findings delimit generality.", "confounders_present": [ "Longer perturbation and direct transcription-factor functions confound geometry; acute Hsieh findings delimit generality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 13, "pmid": "25605944", "title": "Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program.", "citation": "Zhang F, Tanasa B, Merkurjev D et al. Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1424228112", "pmcid": "PMC4321301", "url": "https://pubmed.ncbi.nlm.nih.gov/25605944/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25605944/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25605944", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "corticotrope LDB1 perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Loop-associated LDB1 delivers activating or repressive cargo and affects pausing.", "what_it_does_not_show": "Loops do not universally signify activation; factor-specific biochemical changes remain.", "confounders_present": [ "Loops do not universally signify activation; factor-specific biochemical changes remain." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "39721581", "title": "LDB1 establishes multi-enhancer networks to regulate gene expression.", "citation": "Aboreden NG, Lam JC, Goel VY et al. LDB1 establishes multi-enhancer networks to regulate gene expression. Molecular cell. 2025.", "doi": "10.1016/j.molcel.2024.11.037", "pmcid": "PMC11741933", "url": "https://pubmed.ncbi.nlm.nih.gov/39721581/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39721581/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39229045" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39721581", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "acute erythroid LDB1 degrons and Tri-C", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "LDB1 broadly organizes multi-enhancer connectivity, often independently of CTCF, cohesin and YY1.", "what_it_does_not_show": "Loop assembly and transcription coupling do not establish continuous contact throughout bursts; same lineage as globin platform.", "confounders_present": [ "Loop assembly and transcription coupling do not establish continuous contact throughout bursts; same lineage as globin platform." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "35471149", "title": "Cohesin-dependence of neuronal gene expression relates to chromatin loop length.", "citation": "Calderon L, Weiss FD, Beagan JA et al. Cohesin-dependence of neuronal gene expression relates to chromatin loop length. eLife. 2022.", "doi": "10.7554/eLife.76539", "pmcid": "PMC9106336", "url": "https://pubmed.ncbi.nlm.nih.gov/35471149/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35471149/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35471149", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "primary cortical neuron cohesin deletion", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Long-range neuronal genes depend more on cohesin while immediate-early short contacts and induction persist.", "what_it_does_not_show": "Distance-dependent protein requirement is not a geometry-only or universal burst requirement.", "confounders_present": [ "Distance-dependent protein requirement is not a geometry-only or universal burst requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 16, "pmid": "40239646", "title": "High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH.", "citation": "Zhu Y, Balaji A, Han M et al. High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH. Cell. 2025.", "doi": "10.1016/j.cell.2025.03.032", "pmcid": "PMC12167157", "url": "https://pubmed.ncbi.nlm.nih.gov/40239646/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40239646/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40239646", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Oligo-LiveFISH endogenous FOS imaging", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "High-resolution locus tracking resolves communication modes and transcription-associated slowing.", "what_it_does_not_show": "Method performance and dynamics do not by themselves demonstrate uninterrupted contact necessity.", "confounders_present": [ "Method performance and dynamics do not by themselves demonstrate uninterrupted contact necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 17, "pmid": "27293191", "title": "Enhancer Control of Transcriptional Bursting.", "citation": "Fukaya T, Lim B, Levine M. Enhancer Control of Transcriptional Bursting. Cell. 2016.", "doi": "10.1016/j.cell.2016.05.025", "pmcid": "PMC4970759", "url": "https://pubmed.ncbi.nlm.nih.gov/27293191/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27293191/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27293191", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Drosophila embryonic synthetic reporters", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer strength and insulation mainly alter burst frequency with coordinated linked reporters.", "what_it_does_not_show": "Explicit nonmammalian comparator; does not cross the registered native mammalian threshold.", "confounders_present": [ "Explicit nonmammalian comparator; does not cross the registered native mammalian threshold." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 18, "pmid": "35896525", "title": "Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters.", "citation": "Robles-Rebollo I, Cuartero S, Canellas-Socias A et al. Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters. Nature communications. 2022.", "doi": "10.1038/s41467-022-31192-9", "pmcid": "PMC9329429", "url": "https://pubmed.ncbi.nlm.nih.gov/35896525/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35896525/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35896525", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph21, 1:Results:paragraph22, 1:Results:paragraph26, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "quiescent mouse macrophage native loci", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Cohesin couples enhancer-promoter burst probabilities despite similar measured distances; BD2 inhibition has nonadditive effects.", "what_it_does_not_show": "Fixed RNA-FISH distances and selected induction genes do not resolve ultrabrief DNA contacts; no acute degron used here.", "confounders_present": [ "Fixed RNA-FISH distances and selected induction genes do not resolve ultrabrief DNA contacts; no acute degron used here." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 19, "pmid": "41359380", "title": "Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency.", "citation": "Stumberger G, Hörl D, Tsouraki D et al. Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency. Nucleic acids research. 2025.", "doi": "10.1093/nar/gkaf1255", "pmcid": "PMC12684394", "url": "https://pubmed.ncbi.nlm.nih.gov/41359380/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41359380/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41359380", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "pluripotency transition super-resolution FISH and Tri-C", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Large expression changes often lack median-distance changes; active Nanog and Dppa3 alleles are nearer.", "what_it_does_not_show": "Fixed snapshots support locus-specific association, not causal continuous contact or its total absence.", "confounders_present": [ "Fixed snapshots support locus-specific association, not causal continuous contact or its total absence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 20, "pmid": "40914943", "title": "Real-time visualization of reconstituted transcription reveals RNAPII activation mechanisms at single promoters.", "citation": "Palacio M, Taatjes DJ. Real-time visualization of reconstituted transcription reveals RNAPII activation mechanisms at single promoters. Cell reports. 2025.", "doi": "10.1016/j.celrep.2025.116251", "pmcid": "PMC12520170", "url": "https://pubmed.ncbi.nlm.nih.gov/40914943/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40914943/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39829877" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40914943", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "purified real-time transcription reconstitution", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "IDRs activate polymerase bursting and reinitiation without condensate formation.", "what_it_does_not_show": "Original biochemical research, explicitly outside intact endogenous chromatin; cannot establish native universality.", "confounders_present": [ "Original biochemical research, explicitly outside intact endogenous chromatin; cannot establish native universality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "39642226", "title": "Transcription-coupled changes in genomic region proximities during transcriptional bursting.", "citation": "Ohishi H, Shinkai S, Owada H et al. Transcription-coupled changes in genomic region proximities during transcriptional bursting. Science advances. 2024.", "doi": "10.1126/sciadv.adn0020", "pmcid": "PMC11623302", "url": "https://pubmed.ncbi.nlm.nih.gov/39642226/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39642226/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39642226", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "sequential mouse ESC DNA RNA imaging", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Active gene states correlate with specific proximities and factor accumulation.", "what_it_does_not_show": "Viscosity stabilization is modeled, not a selectively validated causal contact-maintenance mechanism.", "confounders_present": [ "Viscosity stabilization is modeled, not a selectively validated causal contact-maintenance mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "36583343", "title": "Genome-wide inference reveals that feedback regulations constrain promoter-dependent transcriptional burst kinetics.", "citation": "Luo S, Wang Z, Zhang Z et al. Genome-wide inference reveals that feedback regulations constrain promoter-dependent transcriptional burst kinetics. Nucleic acids research. 2023.", "doi": "10.1093/nar/gkac1204", "pmcid": "PMC9874261", "url": "https://pubmed.ncbi.nlm.nih.gov/36583343/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36583343/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36583343", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "mouse fibroblast scRNA inference", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Feedback-stratified inference links enhancer interactions mainly to frequency in positive-feedback contexts.", "what_it_does_not_show": "Indirect kinetic estimation and feedback assumptions prevent direct temporal-contact conclusions.", "confounders_present": [ "Indirect kinetic estimation and feedback assumptions prevent direct temporal-contact conclusions." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 24, "pmid": "38490199", "title": "Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency.", "citation": "Lando D, Ma X, Cao Y et al. Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency. Molecular cell. 2024.", "doi": "10.1016/j.molcel.2024.02.015", "pmcid": "PMC7616059", "url": "https://pubmed.ncbi.nlm.nih.gov/38490199/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38490199/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38490199", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "single-cell mouse pluripotency-exit structures", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Formative state has extensive multiway enhancer-promoter hub reorganization.", "what_it_does_not_show": "Static state association cannot show hubs necessary, sufficient or sustained during bursts.", "confounders_present": [ "Static state association cannot show hubs necessary, sufficient or sustained during bursts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 26, "pmid": "37157000", "title": "Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments.", "citation": "Goel VY, Huseyin MK, Hansen AS. Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments. Nature genetics. 2023.", "doi": "10.1038/s41588-023-01391-1", "pmcid": "PMC10424778", "url": "https://pubmed.ncbi.nlm.nih.gov/37157000/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37157000/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37157000", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC region-capture Micro-C", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Nested microcompartments commonly persist after extrusion loss and transcription inhibition.", "what_it_does_not_show": "Map enrichment and retained contacts cannot establish universal contact dispensability or requirement.", "confounders_present": [ "Map enrichment and retained contacts cannot establish universal contact dispensability or requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 27, "pmid": "25561493", "title": "Initiation and maintenance of pluripotency gene expression in the absence of cohesin.", "citation": "Lavagnolli T, Gupta P, Hörmanseder E et al. Initiation and maintenance of pluripotency gene expression in the absence of cohesin. Genes & development. 2015.", "doi": "10.1101/gad.251835.114", "pmcid": "PMC4281562", "url": "https://pubmed.ncbi.nlm.nih.gov/25561493/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25561493/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25561493", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "heterokaryon and nuclear-transfer reprogramming", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Myc and replication explain context-dependent reprogramming after cohesin loss.", "what_it_does_not_show": "Reprogramming and cell-cycle effects are distinct from same-cell physical burst contacts.", "confounders_present": [ "Reprogramming and cell-cycle effects are distinct from same-cell physical burst contacts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 28, "pmid": "30527662", "title": "Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods.", "citation": "Sun F, Chronis C, Kronenberg M et al. Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2018.10.039", "pmcid": "PMC6338517", "url": "https://pubmed.ncbi.nlm.nih.gov/30527662/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30527662/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30527662", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "ESC Esrrb depletion across neighborhoods", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Esrrb depletion reduces mediator, contacts and expression within selected neighborhoods while flanking genes remain stable.", "what_it_does_not_show": "Enhancer activity and structural contact are perturbed together; geometry-only mediation unresolved.", "confounders_present": [ "Enhancer activity and structural contact are perturbed together; geometry-only mediation unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 29, "pmid": "23665121", "title": "Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming.", "citation": "Apostolou E, Ferrari F, Walsh RM et al. Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell stem cell. 2013.", "doi": "10.1016/j.stem.2013.04.013", "pmcid": "PMC3725985", "url": "https://pubmed.ncbi.nlm.nih.gov/23665121/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23665121/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23665121", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Nanog interactome differentiation and reprogramming", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Interaction changes can precede evident transcriptional and differentiation shifts.", "what_it_does_not_show": "Precedence with multifunctional protein depletion is not continuous contact necessity.", "confounders_present": [ "Precedence with multifunctional protein depletion is not continuous contact necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 30, "pmid": "32213323", "title": "Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding.", "citation": "Hsieh TS, Cattoglio C, Slobodyanyuk E et al. Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding. Molecular cell. 2020.", "doi": "10.1016/j.molcel.2020.03.002", "pmcid": "PMC7703524", "url": "https://pubmed.ncbi.nlm.nih.gov/32213323/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32213323/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32213323", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC Micro-C and transcription inhibition", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Fine transcription-linked structures change when transcription is inhibited while larger architecture persists.", "what_it_does_not_show": "Reverse dependency and drug breadth oppose simple one-way causation; independent contact removal untested.", "confounders_present": [ "Reverse dependency and drug breadth oppose simple one-way causation; independent contact removal untested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 31, "pmid": "28525758", "title": "Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.", "citation": "Nora EP, Goloborodko A, Valton AL et al. Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell. 2017.", "doi": "10.1016/j.cell.2017.05.004", "pmcid": "PMC5538188", "url": "https://pubmed.ncbi.nlm.nih.gov/28525758/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28525758/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28525758", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse CTCF degron and restoration", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CTCF loss and restoration causally alter loops and insulation while compartments persist.", "what_it_does_not_show": "Architectural restoration is not native single-burst DNA contact necessity.", "confounders_present": [ "Architectural restoration is not native single-burst DNA contact necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "34108683", "title": "Defining genome architecture at base-pair resolution.", "citation": "Hua P, Badat M, Hanssen LLP et al. Defining genome architecture at base-pair resolution. Nature. 2021.", "doi": "10.1038/s41586-021-03639-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34108683/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34108683/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34108683", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "base-pair Micro-Capture-C mammalian elements", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Punctate contacts and factor dependence resolve fine regulatory architecture.", "what_it_does_not_show": "High mapping resolution is not continuous same-cell contact or a universal causal endpoint.", "confounders_present": [ "High mapping resolution is not continuous same-cell contact or a universal causal endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "37488417", "title": "Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions.", "citation": "Luo R, Yan J, Oh JW et al. Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions. Nature genetics. 2023.", "doi": "10.1038/s41588-023-01450-7", "pmcid": "PMC11012226", "url": "https://pubmed.ncbi.nlm.nih.gov/37488417/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37488417/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID36945628" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37488417", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human endoderm dynamic CRISPRi screen", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Enhancer impacts are strongest mid-transition; activity-plus-loop model predicts function better than contact frequency.", "what_it_does_not_show": "CRISPRi changes enhancer chemistry; network nonlinearity is not isolated looping causality.", "confounders_present": [ "CRISPRi changes enhancer chemistry; network nonlinearity is not isolated looping causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "24874989", "title": "Role of LDB1 in the transition from chromatin looping to transcription activation.", "citation": "Krivega I, Dale RK, Dean A. Role of LDB1 in the transition from chromatin looping to transcription activation. Genes & development. 2014.", "doi": "10.1101/gad.239749.114", "pmcid": "PMC4066399", "url": "https://pubmed.ncbi.nlm.nih.gov/24874989/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24874989/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24874989", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:Results:paragraph9, 0:Results:paragraph10, 0:Results:paragraph12, 0:Results:paragraph14. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native globin LDB1 mutant rescue", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "DD4/5 deletion restores 3C looping but fails polymerase recruitment and transcription, with stable protein and primary-cell controls.", "what_it_does_not_show": "Mutant changes cofactor delivery; establishes contact alone insufficient, not total contact dispensability.", "confounders_present": [ "Mutant changes cofactor delivery; establishes contact alone insufficient, not total contact dispensability." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 35, "pmid": "22682246", "title": "Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor.", "citation": "Deng W, Lee J, Wang H et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012.", "doi": "10.1016/j.cell.2012.03.051", "pmcid": "PMC3372860", "url": "https://pubmed.ncbi.nlm.nih.gov/22682246/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22682246/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID22682246", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "native globin tethering and internal allele control", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "LDB1 targeting restores contacts, polymerase recruitment and gene output; LCR-deleted allele fails within the same primary cells.", "what_it_does_not_show": "Synthetic active LDB1 tether at an endogenous locus; within-cell enhancer dependence confirms functional specificity but not inert geometric sufficiency or natural continuous-contact necessity.", "confounders_present": [ "Synthetic active LDB1 tether at an endogenous locus; within-cell enhancer dependence confirms functional specificity but not inert geometric sufficiency or natural continuous-contact necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Shared active LDB1 tether platform with 25126789/27067601/27405777/36852088; these are distinct experiments/reports but not independent reagent-class validations." ] }, { "n": 36, "pmid": "28636938", "title": "The LDB1 Complex Co-opts CTCF for Erythroid Lineage-Specific Long-Range Enhancer Interactions.", "citation": "Lee J, Krivega I, Dale RK et al. The LDB1 Complex Co-opts CTCF for Erythroid Lineage-Specific Long-Range Enhancer Interactions. Cell reports. 2017.", "doi": "10.1016/j.celrep.2017.05.072", "pmcid": "PMC5564295", "url": "https://pubmed.ncbi.nlm.nih.gov/28636938/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28636938/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28636938", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native erythroid Car2 and LDB1 CTCF rescue", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Direct LDB1-CTCF interaction and its domain are required for selected contact and expression rescue.", "what_it_does_not_show": "Protein interface dependence combines biochemistry and geometry; selected erythroid scope only.", "confounders_present": [ "Protein interface dependence combines biochemistry and geometry; selected erythroid scope only." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 37, "pmid": "31494034", "title": "Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation.", "citation": "Benabdallah NS, Williamson I, Illingworth RS et al. Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2019.07.038", "pmcid": "PMC6838673", "url": "https://pubmed.ncbi.nlm.nih.gov/31494034/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31494034/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31494034", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph34. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "brain Shh enhancers neural differentiation and embryos", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Enhancer activation increases separation; forced LDB1 looping validates FISH sensitivity, with endogenous factor and catalytic controls.", "what_it_does_not_show": "Brain enhancers differ from limb ZRS; FISH validates detectable forced loops but fixed snapshots do not exclude fleeting productive encounters or contacts before transcription.", "confounders_present": [ "Brain enhancers differ from limb ZRS; FISH validates detectable forced loops but fixed snapshots do not exclude fleeting productive encounters or contacts before transcription." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 38, "pmid": "27867070", "title": "The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances.", "citation": "Symmons O, Pan L, Remeseiro S et al. The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances. Developmental cell. 2016.", "doi": "10.1016/j.devcel.2016.10.015", "pmcid": "PMC5142843", "url": "https://pubmed.ncbi.nlm.nih.gov/27867070/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27867070/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27867070", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse Shh chromosomal rearrangements", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Within-TAD distance changes preserve expression; disruptive inversions alter long-range function.", "what_it_does_not_show": "Domain integrity and genomic distances are changed together; same-cell contact timing untested.", "confounders_present": [ "Domain integrity and genomic distances are changed together; same-cell contact timing untested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 39, "pmid": "40604280", "title": "Range extender mediates long-distance enhancer activity.", "citation": "Bower G, Hollingsworth EW, Jacinto SH et al. Range extender mediates long-distance enhancer activity. Nature. 2025.", "doi": "10.1038/s41586-025-09221-6", "pmcid": "PMC12267059", "url": "https://pubmed.ncbi.nlm.nih.gov/40604280/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40604280/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38826394" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40604280", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse Shh enhancer replacement", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Range-extender sequence confers long-range activation; motif mutants retain short-range but lose long-range function.", "what_it_does_not_show": "Sequence-specific enhancer compatibility, not a direct measurement of sustained contact throughout bursts.", "confounders_present": [ "Sequence-specific enhancer compatibility, not a direct measurement of sustained contact throughout bursts." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "31147463", "title": "Preformed chromatin topology assists transcriptional robustness of Shh during limb development.", "citation": "Paliou C, Guckelberger P, Schöpflin R et al. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1900672116", "pmcid": "PMC6589666", "url": "https://pubmed.ncbi.nlm.nih.gov/31147463/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31147463/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31147463", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse limb Shh topology alleles", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Preformed-loop loss reduces expression without phenotype; hypomorphic enhancer cooperation yields severe loss.", "what_it_does_not_show": "Reinforcement and redundancy support context dependence rather than absolute universal requirement.", "confounders_present": [ "Reinforcement and redundancy support context dependence rather than absolute universal requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 41, "pmid": "31511252", "title": "Developmentally regulated Shh expression is robust to TAD perturbations.", "citation": "Williamson I, Kane L, Devenney PS et al. Developmentally regulated Shh expression is robust to TAD perturbations. Development (Cambridge, England). 2019.", "doi": "10.1242/dev.179523", "pmcid": "PMC7212092", "url": "https://pubmed.ncbi.nlm.nih.gov/31511252/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31511252/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31511252", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse Shh TAD perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Substantial architectural perturbations preserve Shh expression and phenotype except enhancer removal or rare boundary mistargeting.", "what_it_does_not_show": "Residual contacts or alternative routing remain; TAD robustness is not proof of no transient enhancer contact.", "confounders_present": [ "Residual contacts or alternative routing remain; TAD robustness is not proof of no transient enhancer contact." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "40603633", "title": "Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs.", "citation": "Wu H, Zhang J, Tan L et al. Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs. Nature genetics. 2025.", "doi": "10.1038/s41588-025-02247-6", "pmcid": "PMC12283367", "url": "https://pubmed.ncbi.nlm.nih.gov/40603633/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40603633/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40603633", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "single-cell Micro-C multi-enhancer hubs", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-cell maps reveal cohesin-associated stripes and hubs.", "what_it_does_not_show": "Crosslink snapshots and 5-kb bins cannot resolve uninterrupted molecular proximity or causal burst requirement.", "confounders_present": [ "Crosslink snapshots and 5-kb bins cannot resolve uninterrupted molecular proximity or causal burst requirement." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "37012454", "title": "Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion.", "citation": "Zhang S, Übelmesser N, Barbieri M et al. Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Nature genetics. 2023.", "doi": "10.1038/s41588-023-01364-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37012454/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37012454/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37012454", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "RNAPII acute degradation and Micro-C", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Polymerase depletion selectively loses enhancer contacts and rewires extrusion loops while cohesin occupancy persists.", "what_it_does_not_show": "Deleting polymerase removes transcription machinery itself, so contact loss cannot isolate the primary causal direction.", "confounders_present": [ "Deleting polymerase removes transcription machinery itself, so contact loss cannot isolate the primary causal direction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 44, "pmid": "37430091", "title": "RNA polymerase II dynamics shape enhancer-promoter interactions.", "citation": "Barshad G, Lewis JJ, Chivu AG et al. RNA polymerase II dynamics shape enhancer-promoter interactions. Nature genetics. 2023.", "doi": "10.1038/s41588-023-01442-7", "pmcid": "PMC10714922", "url": "https://pubmed.ncbi.nlm.nih.gov/37430091/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37430091/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37430091", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Micro-C CRISPRi and polymerase dynamics", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Paused polymerase partly stabilizes functional regulatory interactions.", "what_it_does_not_show": "Chemistry and contact dynamics reciprocally change; geometry-only necessity remains unresolved.", "confounders_present": [ "Chemistry and contact dynamics reciprocally change; geometry-only necessity remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "27067601", "title": "Enhancer Regulation of Transcriptional Bursting Parameters Revealed by Forced Chromatin Looping.", "citation": "Bartman CR, Hsu SC, Hsiung CC et al. Enhancer Regulation of Transcriptional Bursting Parameters Revealed by Forced Chromatin Looping. Molecular cell. 2016.", "doi": "10.1016/j.molcel.2016.03.007", "pmcid": "PMC4842148", "url": "https://pubmed.ncbi.nlm.nih.gov/27067601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27067601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27067601", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph11, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse and human globin RNA-FISH", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Forced contacts increase burst fraction without size; LCR deletion affects both; competing promoters disfavor cis cotranscription.", "what_it_does_not_show": "Synthetic protein tether at native locus; snapshot burst fraction is not direct burst frequency; paper reserves definitive switching kinetics for live imaging.", "confounders_present": [ "Synthetic protein tether at native locus; snapshot burst fraction is not direct burst frequency; paper reserves definitive switching kinetics for live imaging." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Same active globin tether chemistry; new RNA-FISH readout is not independent reagent validation." ] }, { "n": 46, "pmid": "39626660", "title": "Long-range regulation of transcription scales with genomic distance in a gene-specific manner.", "citation": "Jensen CL, Chen LF, Swigut T et al. Long-range regulation of transcription scales with genomic distance in a gene-specific manner. Molecular cell. 2025.", "doi": "10.1016/j.molcel.2024.10.021", "pmcid": "PMC11741922", "url": "https://pubmed.ncbi.nlm.nih.gov/39626660/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39626660/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID39071420" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39626660", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native Prdm8 Fgf5 synthetic activator recruitment", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Gene-specific expression-distance scaling cannot be explained by contact frequency, promoter sequence or measured repressive marks.", "what_it_does_not_show": "Synthetic activator chemistry and native locus differ; universal distance law unsupported.", "confounders_present": [ "Synthetic activator chemistry and native locus differ; universal distance law unsupported." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "39626663", "title": "Enhancer cooperativity can compensate for loss of activity over large genomic distances.", "citation": "Thomas HF, Feng S, Haslhofer F et al. Enhancer cooperativity can compensate for loss of activity over large genomic distances. Molecular cell. 2025.", "doi": "10.1016/j.molcel.2024.11.008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39626663/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39626663/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39626663", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic mouse enhancer landscapes", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "A weak intervening enhancer compensates distance loss through context-dependent cooperation.", "what_it_does_not_show": "Artificial two-enhancer platform; neither native constant contact nor a unique enhancer class demonstrated.", "confounders_present": [ "Artificial two-enhancer platform; neither native constant contact nor a unique enhancer class demonstrated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 48, "pmid": "36323252", "title": "Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription.", "citation": "Reed KSM, Davis ES, Bond ML et al. Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription. Cell reports. 2022.", "doi": "10.1016/j.celrep.2022.111567", "pmcid": "PMC9707392", "url": "https://pubmed.ncbi.nlm.nih.gov/36323252/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36323252/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36323252", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "eight-timepoint macrophage activation maps", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer acetylation precedes expression and transcription can impede loop formation.", "what_it_does_not_show": "Temporal inference is reciprocal association without selective same-cell contact loss.", "confounders_present": [ "Temporal inference is reciprocal association without selective same-cell contact loss." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 49, "pmid": "38372567", "title": "The impact of genomic distance on enhancer-promoter interactions at the CFTR locus.", "citation": "Kerschner JL, Meckler F, Coatti GC et al. The impact of genomic distance on enhancer-promoter interactions at the CFTR locus. Journal of cellular and molecular medicine. 2024.", "doi": "10.1111/jcmm.18142", "pmcid": "PMC10875976", "url": "https://pubmed.ncbi.nlm.nih.gov/38372567/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38372567/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38372567", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "native airway and intestinal CFTR deletions", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Spacing edits affect contact and expression differently by cell type and deletion size.", "what_it_does_not_show": "Clonal variation and deleted sequences confound a universal geometry-only conclusion.", "confounders_present": [ "Clonal variation and deleted sequences confound a universal geometry-only conclusion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "38084924", "title": "Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries.", "citation": "Balasubramanian D, Borges Pinto P, Grasso A et al. Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries. Nucleic acids research. 2024.", "doi": "10.1093/nar/gkad1183", "pmcid": "PMC10899756", "url": "https://pubmed.ncbi.nlm.nih.gov/38084924/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38084924/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38084924", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "Drosophila twist enhancer relocation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Inter-TAD contacts can form yet are functionally limited and not purely distance-determined.", "what_it_does_not_show": "Explicit nonmammalian comparator; topology and enhancer relocation change more than proximity.", "confounders_present": [ "Explicit nonmammalian comparator; topology and enhancer relocation change more than proximity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "42449150", "title": "Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts.", "citation": "Tünnermann J, Roth G, Cramard J et al. Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts. Nature genetics. 2026.", "doi": "10.1038/s41588-026-02676-x", "pmcid": "PMC13447087", "url": "https://pubmed.ncbi.nlm.nih.gov/42449150/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42449150/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42449150", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered mammalian live reporter landscapes", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer position modulates clusters of bursts and active-regime entry.", "what_it_does_not_show": "2026 final publication supersedes provider 2025 label; simplified landscape does not establish native continuous-contact necessity.", "confounders_present": [ "2026 final publication supersedes provider 2025 label; simplified landscape does not establish native continuous-contact necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Related simplified landscape platform to 35418676; live kinetics adds information but shares synthetic regulatory context." ] }, { "n": 53, "pmid": "32958948", "title": "Single-gene imaging links genome topology, promoter-enhancer communication and transcription control.", "citation": "Li J, Hsu A, Hua Y et al. Single-gene imaging links genome topology, promoter-enhancer communication and transcription control. Nature structural & molecular biology. 2020.", "doi": "10.1038/s41594-020-0493-6", "pmcid": "PMC7644657", "url": "https://pubmed.ncbi.nlm.nih.gov/32958948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32958948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32958948", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC native gene nanoscopy", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer clusters reside within regulatory-factor clustering distances of target genes.", "what_it_does_not_show": "Nanoenvironment proximity does not show direct uninterrupted DNA tethering as the causal switch.", "confounders_present": [ "Nanoenvironment proximity does not show direct uninterrupted DNA tethering as the causal switch." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 54, "pmid": "38781242", "title": "Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity.", "citation": "Gómez Acuña LI, Flyamer I, Boyle S et al. Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity. PLoS genetics. 2024.", "doi": "10.1371/journal.pgen.1011277", "pmcid": "PMC11152312", "url": "https://pubmed.ncbi.nlm.nih.gov/38781242/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38781242/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38781242", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native GREB1 NRIP1 enhancer deletions and inhibitors", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Activation raises ligation contacts while increasing FISH distance; two inhibitors separate transcription-dependent distance from contacts.", "what_it_does_not_show": "Fixed complementary assays do not measure the same contact trajectory; two loci and cancer-derived cells delimit scope.", "confounders_present": [ "Fixed complementary assays do not measure the same contact trajectory; two loci and cancer-derived cells delimit scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 55, "pmid": "42637758", "title": "Cohesin acts as a transcriptional gatekeeper by restraining pause-release to promote processive elongation.", "citation": "Tei S, Bando M, Sakata T et al. Cohesin acts as a transcriptional gatekeeper by restraining pause-release to promote processive elongation. Nature communications. 2026.", "doi": "10.1038/s41467-026-76738-3", "pmcid": "PMC13503787", "url": "https://pubmed.ncbi.nlm.nih.gov/42637758/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42637758/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42637758", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human cohesin transcription kinetic perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Reduced recruitment and increased pause release can compensate after cohesin loss, while induction and processivity suffer.", "what_it_does_not_show": "Model and protein perturbation separate transcription steps rather than selectively abolishing continuous DNA contact.", "confounders_present": [ "Model and protein perturbation separate transcription steps rather than selectively abolishing continuous DNA contact." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 56, "pmid": "35710842", "title": "Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes.", "citation": "Rinzema NJ, Sofiadis K, Tjalsma SJD et al. Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes. Nature structural & molecular biology. 2022.", "doi": "10.1038/s41594-022-00787-7", "pmcid": "PMC9205769", "url": "https://pubmed.ncbi.nlm.nih.gov/35710842/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35710842/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35710842", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "synthetic bottom-up mammalian landscapes", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer recruits cohesin and needs it for distal but not proximal gene activation.", "what_it_does_not_show": "Engineered inactive chromatin and promoter context prevent universal native-loop transfer.", "confounders_present": [ "Engineered inactive chromatin and promoter context prevent universal native-loop transfer." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "33398174", "title": "Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation.", "citation": "Kubo N, Ishii H, Xiong X et al. Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation. Nature structural & molecular biology. 2021.", "doi": "10.1038/s41594-020-00539-5", "pmcid": "PMC7913465", "url": "https://pubmed.ncbi.nlm.nih.gov/33398174/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33398174/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33398174", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC neural transition CTCF site and tethering", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Promoter CTCF disruption reduces distal contacts and expression; tethering restores both.", "what_it_does_not_show": "CTCF also has direct promoter functions, isolated later by Narita; contact-only mediation unresolved.", "confounders_present": [ "CTCF also has direct promoter functions, isolated later by Narita; contact-only mediation unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "28985562", "title": "Cohesin Loss Eliminates All Loop Domains.", "citation": "Rao SSP, Huang SC, Glenn St Hilaire B et al. Cohesin Loss Eliminates All Loop Domains. Cell. 2017.", "doi": "10.1016/j.cell.2017.09.026", "pmcid": "PMC5846482", "url": "https://pubmed.ncbi.nlm.nih.gov/28985562/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28985562/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28985562", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human acute cohesin removal and restoration", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Loop domains disappear and reform; most expression remains with selected changes and superenhancer colocalization.", "what_it_does_not_show": "Structural loops and enhancer contacts differ; minority effects and retained compartments require scope labels.", "confounders_present": [ "Structural loops and enhancer contacts differ; minority effects and retained compartments require scope labels." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 59, "pmid": "30554946", "title": "Transcriptional Burst Initiation and Polymerase Pause Release Are Key Control Points of Transcriptional Regulation.", "citation": "Bartman CR, Hamagami N, Keller CA et al. Transcriptional Burst Initiation and Polymerase Pause Release Are Key Control Points of Transcriptional Regulation. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2018.11.004", "pmcid": "PMC6368450", "url": "https://pubmed.ncbi.nlm.nih.gov/30554946/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30554946/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30554946", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "single-cell transcription regulatory perturbations", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Burst initiation and pause release are separate regulatory control points.", "what_it_does_not_show": "No direct enhancer contact duration measurement; informs biochemical rival rather than contact absence.", "confounders_present": [ "No direct enhancer contact duration measurement; informs biochemical rival rather than contact absence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "42607687", "title": "Single-cell 3D genome imaging shows super-enhancer hubs are rare, nonspecific, and neither necessary nor sufficient for transcriptional bursting.", "citation": "Le DJ, Hafner A, Raja Venkatesh A et al. Single-cell 3D genome imaging shows super-enhancer hubs are rare, nonspecific, and neither necessary nor sufficient for transcriptional bursting. Cell genomics. 2026.", "doi": "10.1016/j.xgen.2026.101331", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42607687", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC multiplexed DNA and nascent RNA imaging", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Hubs are rare and promiscuous, with bursts lacking hubs and weak probability enhancement in larger hubs.", "what_it_does_not_show": "Fixed snapshots and selected cell state do not exclude pairwise transient contacts or all enhancer cooperation.", "confounders_present": [ "Fixed snapshots and selected cell state do not exclude pairwise transient contacts or all enhancer cooperation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 62, "verified": 62, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Genome-wide association and colocalization without direct perturbation cap at Β.", "specific_trigger": "Orthogonal regulatory contact maps and native imaging establish enrichment and spatial organization, with locus/state exceptions. Association establishes the observation without causal transfer; Β is retained.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC2", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Overexpression in model systems caps at Γ", "specific_trigger": "LDB1 tethering activates selected silent native globin promoters with enhancer-deletion and targeting controls. This is causal engineered intervention, but the exact index states synthetic-tether sufficiency is governed by the non-endogenous cap; Γ limits its inference to natural looping. Loop-competent activation-defective rescue also proves geometry alone is not sufficient.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Reporter-construct behavior alone", "specific_trigger": "Forced native-globin tethers alter snapshot burst fraction and ectopic graded landscapes fit promoter on-rate modulation. Neither measures selectively varied native contact probability with direct live burst frequency; active tether chemistry, distance changes and synthetic context remain. The broad registered claim retains Γ, with causal engineered output acknowledged separately.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Physical enhancer-promoter looping is required to initiate and maintain transcriptional bursting rather than being a correlate of activity.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The exact hypothesis index governs SC2 synthetic-tether sufficiency: its non-endogenous cap is Γ even when the targeted gene is endogenous. The native locus does not make the engineered active tether endogenous. SC4 snapshot burst fraction and ectopic position platforms support mechanism but cannot transfer a positive frequency law to native contact dynamics. SC3 contrary results trigger a single downgrade from Γ to Β; acute cohesin removal is explicitly not total contact ablation.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Loop or contact enrichment alone" ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Orthogonal regulatory contact maps and native imaging establish enrichment and spatial organization, with locus/state exceptions. Association establishes the observation without causal transfer; Β is retained.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Synthetic active tether: exact index non-endogenous cap; endogenous target does not establish endogenous geometry-only sufficiency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "LDB1 tethering activates selected silent native globin promoters with enhancer-deletion and targeting controls. This is causal engineered intervention, but the exact index states synthetic-tether sufficiency is governed by the non-endogenous cap; Γ limits its inference to natural looping. Loop-competent activation-defective rescue also proves geometry alone is not sufficient.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "No positive endogenous selective contact-release/rescue crossing; index-directed contrary native predictions cause one subsequent Γ-to-Β downgrade." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "No positive selective release/rescue test establishes uninterrupted native contact through both initiation and maintenance. The exact index mandates a falsification pattern for contrary endogenous predictions. Apply one downgrade from mechanistic Γ to Β, retaining reporter delay, label offset and unresolved ultrabrief encounters rather than asserting zero contacts.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Reporter-construct behavior alone", "Snapshot burst fraction and modeled on-rates do not establish isolated native frequency control." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Forced native-globin tethers alter snapshot burst fraction and ectopic graded landscapes fit promoter on-rate modulation. Neither measures selectively varied native contact probability with direct live burst frequency; active tether chemistry, distance changes and synthetic context remain. The broad registered claim retains Γ, with causal engineered output acknowledged separately.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Reproducible orthogonal contact measurements with matched genomic-distance and chromatin-state controls, followed by selective functional perturbation for causal inference." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Inert inducible proximity with inactive-tether, enhancer deletion and recruitment controls at multiple native silent genes; separate biochemical activation from geometry." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Same-allele rapid selective contact release and re-establishment during initiation and active bursts while enhancer chemistry, TF occupancy and polymerase competence remain unchanged, with calibrated molecular-resolution contact detection." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Native graded contact probability alteration independently of enhancer strength, directly measured initiation frequency and active duration, rescue and orthogonal assay replication." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Deng within-cell LCR-deleted allele and nonfunctional targeting controls distinguish long-range enhancer dependence from generic promoter recruitment.", "Krivega stable loop-competent activation-defective mutant and primary-cell rescue distinguish proximity from downstream chemistry.", "Alexander SCR deletion, transcription block, no-MS2 and shortened-distance controls validate output and geometry, while label offsets are retained.", "Estrogen enhancer-deletion cross-locus controls, smaller probes and two transcription inhibitors separate assay observables." ], "note": "Mammalian native loci are the gate; engineered reporters, purified systems and two Drosophila comparators are explicitly outside that crossing. Brain versus limb enhancers, quiescent macrophages versus ESC maintenance, genomic distance and activation history are defined before interpreting response. No responder-only population is invented." }, "falsification_patterns_met": [ { "pattern": "Endogenous tests contradict in vitro predictions", "evidence": "The exact index specifically directs continuous-contact SC3 contradictions to be treated as falsification. Native Sox2 measured proximity does not predict enhancer-dependent bursts; neural Shh and estrogen loci show activation with increased spatial separation. Detection limitations are retained. These correlated versions of one sustained-contact prediction are counted once; cohesin-depletion retained contacts are not themselves contact-ablation falsification.", "downgrade_applied": true, "from_level": "Γ", "to_level": "Β", "subclaim_id": "SC3" } ], "pitfalls_flagged": [ { "pitfall": "Extrusion loss equated with enhancer-contact loss", "where": "Hsieh retains most enhancer contacts, so its transcription persistence does not isolate contact dispensability." }, { "pitfall": "Burst fraction called frequency", "where": "Bartman measures snapshot occupancy; frequency and duration cannot be identified without temporal kinetics." }, { "pitfall": "Preprint and publication-year substitution", "where": "Yang, Cheng and Ubertini/Foldes are not counted as peer-reviewed; Alexander, Du, Goel, Zhang and Tunnermann use canonical publication years." }, { "pitfall": "Different Shh enhancers conflated", "where": "Benabdallah brain enhancers and limb ZRS topology are separate scopes." } ], "causal_tally_audit": { "tally_claimed_by_document": 0, "tally_after_audit": 0, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 12, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "One rung above, Γ: active native-locus tethers and graded synthetic landscapes establish a plausible route from encounters to output, and finite imaging resolution leaves undetected brief interactions possible. However, the scored proposition requires continuous contact throughout initiation and maintenance; the exact index directs the contrary native predictions to count as falsification, so plausibility alone cannot cancel the one-rung downgrade.", "case_one_rung_lower": "One rung below, Α: sustained-loop language can operate as a descriptive metaphor and fails several native predictions. Yet measured regulatory contacts and functional looping interventions provide a substantive biological mechanism; the observation is not mere narrative. A single falsification pattern is counted once, not repeatedly for correlated assays or every contrary paper.", "which_rejected": "Retain Β for continuous-contact necessity after one explicit Γ-to-Β falsification downgrade. Contact existence retains Β; synthetic sufficiency and graded burst modulation retain Γ for inference to the registered endogenous mammalian claim. Narrow native architecture/output contributions remain real and do not rescue universal continuous contact.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: At several prespecified native mammalian loci, combine molecular-resolution same-allele contact and nascent initiation tracking with rapidly reversible contact-selective tether release while preserving enhancer activity, local factor occupancy and transcriptional competence." }, "final_score": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the band, not correctness and not reviewer access depth: the contact-enrichment and architecture literatures are large and replicated across orthogonal assay classes, while the decisive native-geometry measurements sit at the edge of their own detection limits, the strongest positive interventions share one tether reagent platform, several key results come from synthetic or ectopic landscapes, and burst fraction repeatedly stands in for burst frequency.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered primary SC3 necessity gate is Β: partial mechanistic plausibility is capped at Γ, then one endogenous-prediction falsification pattern lowers it one rung. Native Sox2 simultaneous imaging and orthogonal neural Shh/estrogen distance findings oppose the universal sustained-contact prediction within detection limits. This is neither proof that brief contacts never occur nor a denial of causal enhancer function. Exact index additionally restricts synthetic SC2 sufficiency to Γ; broad SC4 graded frequency remains Γ because its strongest controlled tests use synthetic tethers/landscapes and snapshot or inferred kinetics." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Transcription can influence contact, but is not its sole producer (step1). Functional native contact interventions establish contributions (step2). Universal uninterrupted primary initiation and rate limitation are absent (step3), as is universal contact necessity (step4). Defined looping raises burst participation and topology reinforces robustness (step5); the classification describes demonstrated contact contributions, not proof of the sustained-switch hypothesis.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent 2025/2026 imaging and kinetic reports address mechanisms; no verified ongoing decisive contact-release experiment is asserted.", "justification": "Recent 2025/2026 imaging and kinetic reports address mechanisms; no verified ongoing decisive contact-release experiment is asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Β", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": true, "prior_level": "Γ", "prior_confidence": "Moderate", "prior_source": "prior-edition/enhancer-promoter-looping.scorecard.json", "derived_before_consulting_prior": true, "new_level": "Β", "direction": "lowered", "what_moved_it": "Independent lock precedes prior consultation. Exact-index endogenous falsification applies once to SC3 (Γ to Β); SC2 synthetic tether cap and SC4 snapshot frequency limitation are corrected. 57 empirical primary reports retain historical reference numbering; surrounding prior prose preserved and correction log attached.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "At several prespecified native mammalian loci, combine molecular-resolution same-allele contact and nascent initiation tracking with rapidly reversible contact-selective tether release while preserving enhancer activity, local factor occupancy and transcriptional competence.", "readout": "Contact dwell, initiation time, active burst duration and nascent output after selective release and restoration", "critical_control": "Orthogonal labels, calibrated label offsets and encounter detection, inactive tether and enhancer-deletion controls, matched factor occupancy and viability", "supporting_result": "Contact loss immediately prevents initiation and terminates active bursts across prespecified loci, with specific reversible rescue", "falsifying_result": "New bursts or maintenance persist after verified contact loss with competent machinery, or only encounter probability rather than sustained dwell controls output" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Resolve fleeting productive encounters versus sustained molecular contact with calibrated label offsets and subsecond detection.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Separate burst frequency, burst occupancy, burst-cluster entry and active duration using live kinetics.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Develop contact-selective perturbation with enhancer and polymerase chemistry preserved.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Quantify transcriptional memory after contacts end at native loci.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Test initiation and maintenance separately in naive versus induced states and differentiated cells.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Reconcile assay-specific ligation enrichment and physical-distance distributions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Audit the Du and Narita correction bodies and full supplements before publication-grade quantitative claims.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-12", "reviewer": "Codex", "evidence_base_note": "57 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite is queried per case where connected; received tallies/outgoing reference contexts are not audited incoming contrasting statements. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review. Enhancer Scite exact-DOI attempt returned monthly quota error, with no returned tally/context. Current checkpoint uses copied immutable original retrieval artifacts plus fresh presentation receipts. The prior narrative remains unchanged outside the three scoring blocks; its three background entries carry no current primary credit.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Endogenous acute degrons, locus-specific allele edits, dose/distance engineering and orthogonal live/fixed/contact-mapping measurements were considered. They demonstrate selected architecture or biochemical contributions and narrow alternatives, but no positive contact-selective release/rescue test establishes continuous-contact necessity throughout native initiation and maintenance. Synthetic active tethers cannot alone rescue native necessity; convergent null/challenge results are not positive threshold crossings. Upper rungs remain reachable for a properly isolated same-scope dependency." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous acute degrons, locus-specific allele edits, dose/distance engineering and orthogonal live/fixed/contact-mapping measurements were considered. They demonstrate selected architecture or biochemical contributions and narrow alternatives, but no positive contact-selective release/rescue test establishes continuous-contact necessity throughout native initiation and maintenance. Synthetic active tethers cannot alone rescue native necessity; convergent null/challenge results are not positive threshold crossings. Upper rungs remain reachable for a properly isolated same-scope dependency." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous acute degrons, locus-specific allele edits, dose/distance engineering and orthogonal live/fixed/contact-mapping measurements were considered. They demonstrate selected architecture or biochemical contributions and narrow alternatives, but no positive contact-selective release/rescue test establishes continuous-contact necessity throughout native initiation and maintenance. Synthetic active tethers cannot alone rescue native necessity; convergent null/challenge results are not positive threshold crossings. Upper rungs remain reachable for a properly isolated same-scope dependency." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous acute degrons, locus-specific allele edits, dose/distance engineering and orthogonal live/fixed/contact-mapping measurements were considered. They demonstrate selected architecture or biochemical contributions and narrow alternatives, but no positive contact-selective release/rescue test establishes continuous-contact necessity throughout native initiation and maintenance. Synthetic active tethers cannot alone rescue native necessity; convergent null/challenge results are not positive threshold crossings. Upper rungs remain reachable for a properly isolated same-scope dependency." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous acute degrons, locus-specific allele edits, dose/distance engineering and orthogonal live/fixed/contact-mapping measurements were considered. They demonstrate selected architecture or biochemical contributions and narrow alternatives, but no positive contact-selective release/rescue test establishes continuous-contact necessity throughout native initiation and maintenance. Synthetic active tethers cannot alone rescue native necessity; convergent null/challenge results are not positive threshold crossings. Upper rungs remain reachable for a properly isolated same-scope dependency." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 57, "claims_total": 62, "claims_verified": 62, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 57, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Condensate distance predicts burst enhancement better than enhancer distance; basal bursts persist. Condensate geometry is not direct DNA-contact necessity; linked correction body remains unexamined.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Enhancer-dependent native Sox2 bursts show no contemporaneous, tested lag-window or cell-average relation to measured enhancer proximity. Labels are kilobases from elements, finite resolution and 0.5–2-minute reporter delay leave ultrabrief or earlier contacts possible; imaging null is a prediction challenge, not direct selective contact-ablation proof.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph20, 1:Results:paragraph42, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "Targeted globin looping raises fetal hemoglobin and reduces sickling with low measured toxicity. Shared LDB1 platform; ex vivo efficacy does not measure continuous same-cell contact.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Tethered LDB1 reactivates silenced globin genes, depends on LCR and redirects promoter contacts. Tether is a functional protein domain rather than inert geometry; continuous necessity untested.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "Rewiring raises fetal globin in two transplanted animal settings. Shared reagent; engineered graft output does not establish universal mammalian promoter mechanism.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "TATA deletion stops transcription while contact remains; activation-deficient LDB1 restores loops without mediator or cohesin. Disentangles transcription machinery from looping; does not prove all contacts unnecessary.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Most enhancer-promoter contacts and transcription persist after acute extrusion-factor loss; TF binding decreases. Contacts largely remain, so depletion is not a selective contact-ablation necessity test; short window and thresholds matter.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph21, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "CBP/p300 target stratification detects reproducible subtle cohesin effects; loop-defective CTCF retains promoter activation. Constitutive mutant adaptation, response thresholds and linked unexamined correction limit detailed attribution.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph23, 1:Results:paragraph25, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "ZNF143 binds directional sites and affects looping and CTCF/cohesin arrangement. DNA binding and promoter activity change with geometry; uninterrupted contact requirement is not isolated.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Contact probability relates nonlinearly to reporter output and inferred promoter on-rate with alternative-model controls. Founder-line contact probabilities and simplified ectopic locus do not directly track native contact during individual bursts.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 2:Enhancer contacts modulate burst frequency:paragraph0, 2:Enhancer contacts modulate burst frequency:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Cell-type contacts accompany expression; activation alone does not create TAD boundaries. Temporal covariation and maps cannot isolate uninterrupted burst contact causality.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "YY1 site deletion or depletion alters contacts and expression. Longer perturbation and direct transcription-factor functions confound geometry; acute Hsieh findings delimit generality.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Loop-associated LDB1 delivers activating or repressive cargo and affects pausing. Loops do not universally signify activation; factor-specific biochemical changes remain.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "LDB1 broadly organizes multi-enhancer connectivity, often independently of CTCF, cohesin and YY1. Loop assembly and transcription coupling do not establish continuous contact throughout bursts; same lineage as globin platform.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "Long-range neuronal genes depend more on cohesin while immediate-early short contacts and induction persist. Distance-dependent protein requirement is not a geometry-only or universal burst requirement.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "High-resolution locus tracking resolves communication modes and transcription-associated slowing. Method performance and dynamics do not by themselves demonstrate uninterrupted contact necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Enhancer strength and insulation mainly alter burst frequency with coordinated linked reporters. Explicit nonmammalian comparator; does not cross the registered native mammalian threshold.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Cohesin couples enhancer-promoter burst probabilities despite similar measured distances; BD2 inhibition has nonadditive effects. Fixed RNA-FISH distances and selected induction genes do not resolve ultrabrief DNA contacts; no acute degron used here.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph21, 1:Results:paragraph22, 1:Results:paragraph26, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "Large expression changes often lack median-distance changes; active Nanog and Dppa3 alleles are nearer. Fixed snapshots support locus-specific association, not causal continuous contact or its total absence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "IDRs activate polymerase bursting and reinitiation without condensate formation. Original biochemical research, explicitly outside intact endogenous chromatin; cannot establish native universality.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Active gene states correlate with specific proximities and factor accumulation. Viscosity stabilization is modeled, not a selectively validated causal contact-maintenance mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "Feedback-stratified inference links enhancer interactions mainly to frequency in positive-feedback contexts. Indirect kinetic estimation and feedback assumptions prevent direct temporal-contact conclusions.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "Formative state has extensive multiway enhancer-promoter hub reorganization. Static state association cannot show hubs necessary, sufficient or sustained during bursts.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "Nested microcompartments commonly persist after extrusion loss and transcription inhibition. Map enrichment and retained contacts cannot establish universal contact dispensability or requirement.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "Myc and replication explain context-dependent reprogramming after cohesin loss. Reprogramming and cell-cycle effects are distinct from same-cell physical burst contacts.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "Esrrb depletion reduces mediator, contacts and expression within selected neighborhoods while flanking genes remain stable. Enhancer activity and structural contact are perturbed together; geometry-only mediation unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "Interaction changes can precede evident transcriptional and differentiation shifts. Precedence with multifunctional protein depletion is not continuous contact necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "Fine transcription-linked structures change when transcription is inhibited while larger architecture persists. Reverse dependency and drug breadth oppose simple one-way causation; independent contact removal untested.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "CTCF loss and restoration causally alter loops and insulation while compartments persist. Architectural restoration is not native single-burst DNA contact necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "Punctate contacts and factor dependence resolve fine regulatory architecture. High mapping resolution is not continuous same-cell contact or a universal causal endpoint.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "Enhancer impacts are strongest mid-transition; activity-plus-loop model predicts function better than contact frequency. CRISPRi changes enhancer chemistry; network nonlinearity is not isolated looping causality.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "DD4/5 deletion restores 3C looping but fails polymerase recruitment and transcription, with stable protein and primary-cell controls. Mutant changes cofactor delivery; establishes contact alone insufficient, not total contact dispensability.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Results:paragraph9, 0:Results:paragraph10, 0:Results:paragraph12, 0:Results:paragraph14. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "LDB1 targeting restores contacts, polymerase recruitment and gene output; LCR-deleted allele fails within the same primary cells. Synthetic active LDB1 tether at an endogenous locus; within-cell enhancer dependence confirms functional specificity but not inert geometric sufficiency or natural continuous-contact necessity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "Direct LDB1-CTCF interaction and its domain are required for selected contact and expression rescue. Protein interface dependence combines biochemistry and geometry; selected erythroid scope only.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "Enhancer activation increases separation; forced LDB1 looping validates FISH sensitivity, with endogenous factor and catalytic controls. Brain enhancers differ from limb ZRS; FISH validates detectable forced loops but fixed snapshots do not exclude fleeting productive encounters or contacts before transcription.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph34. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Within-TAD distance changes preserve expression; disruptive inversions alter long-range function. Domain integrity and genomic distances are changed together; same-cell contact timing untested.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "Range-extender sequence confers long-range activation; motif mutants retain short-range but lose long-range function. Sequence-specific enhancer compatibility, not a direct measurement of sustained contact throughout bursts.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "Preformed-loop loss reduces expression without phenotype; hypomorphic enhancer cooperation yields severe loss. Reinforcement and redundancy support context dependence rather than absolute universal requirement.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "Substantial architectural perturbations preserve Shh expression and phenotype except enhancer removal or rare boundary mistargeting. Residual contacts or alternative routing remain; TAD robustness is not proof of no transient enhancer contact.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "Single-cell maps reveal cohesin-associated stripes and hubs. Crosslink snapshots and 5-kb bins cannot resolve uninterrupted molecular proximity or causal burst requirement.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "Polymerase depletion selectively loses enhancer contacts and rewires extrusion loops while cohesin occupancy persists. Deleting polymerase removes transcription machinery itself, so contact loss cannot isolate the primary causal direction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "Paused polymerase partly stabilizes functional regulatory interactions. Chemistry and contact dynamics reciprocally change; geometry-only necessity remains unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "Forced contacts increase burst fraction without size; LCR deletion affects both; competing promoters disfavor cis cotranscription. Synthetic protein tether at native locus; snapshot burst fraction is not direct burst frequency; paper reserves definitive switching kinetics for live imaging.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph11, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "Gene-specific expression-distance scaling cannot be explained by contact frequency, promoter sequence or measured repressive marks. Synthetic activator chemistry and native locus differ; universal distance law unsupported.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "A weak intervening enhancer compensates distance loss through context-dependent cooperation. Artificial two-enhancer platform; neither native constant contact nor a unique enhancer class demonstrated.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Enhancer acetylation precedes expression and transcription can impede loop formation. Temporal inference is reciprocal association without selective same-cell contact loss.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "Spacing edits affect contact and expression differently by cell type and deletion size. Clonal variation and deleted sequences confound a universal geometry-only conclusion.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "Inter-TAD contacts can form yet are functionally limited and not purely distance-determined. Explicit nonmammalian comparator; topology and enhancer relocation change more than proximity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "Enhancer position modulates clusters of bursts and active-regime entry. 2026 final publication supersedes provider 2025 label; simplified landscape does not establish native continuous-contact necessity.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Enhancer clusters reside within regulatory-factor clustering distances of target genes. Nanoenvironment proximity does not show direct uninterrupted DNA tethering as the causal switch.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Activation raises ligation contacts while increasing FISH distance; two inhibitors separate transcription-dependent distance from contacts. Fixed complementary assays do not measure the same contact trajectory; two loci and cancer-derived cells delimit scope.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "Reduced recruitment and increased pause release can compensate after cohesin loss, while induction and processivity suffer. Model and protein perturbation separate transcription steps rather than selectively abolishing continuous DNA contact.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Enhancer recruits cohesin and needs it for distal but not proximal gene activation. Engineered inactive chromatin and promoter context prevent universal native-loop transfer.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Promoter CTCF disruption reduces distal contacts and expression; tethering restores both. CTCF also has direct promoter functions, isolated later by Narita; contact-only mediation unresolved.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Loop domains disappear and reform; most expression remains with selected changes and superenhancer colocalization. Structural loops and enhancer contacts differ; minority effects and retained compartments require scope labels.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "Burst initiation and pause release are separate regulatory control points. No direct enhancer contact duration measurement; informs biochemical rival rather than contact absence.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C57", "text": "Hubs are rare and promiscuous, with bursts lacking hubs and weak probability enhancement in larger hubs. Fixed snapshots and selected cell state do not exclude pairwise transient contacts or all enhancer cooperation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "Orthogonal regulatory contact maps and native imaging establish enrichment and spatial organization, with locus/state exceptions. Association establishes the observation without causal transfer; Β is retained.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 2, 7, 9, 11, 12, 14, 16, 19, 21, 24, 26, 28, 29, 30, 31, 32, 37, 42, 43, 44, 48, 51, 53, 54, 58, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "LDB1 tethering activates selected silent native globin promoters with enhancer-deletion and targeting controls. This is causal engineered intervention, but the exact index states synthetic-tether sufficiency is governed by the non-endogenous cap; Γ limits its inference to natural looping. Loop-competent activation-defective rescue also proves geometry alone is not sufficient.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3, 4, 5, 6, 34, 35, 36, 39, 45, 56, 57 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "No positive selective release/rescue test establishes uninterrupted native contact through both initiation and maintenance. The exact index mandates a falsification pattern for contrary endogenous predictions. Apply one downgrade from mechanistic Γ to Β, retaining reporter delay, label offset and unresolved ultrabrief encounters rather than asserting zero contacts.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 6, 7, 8, 9, 12, 13, 14, 15, 16, 18, 19, 20, 21, 26, 27, 28, 29, 30, 31, 33, 34, 36, 37, 38, 40, 41, 43, 44, 48, 49, 53, 54, 55, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC4", "text": "Forced native-globin tethers alter snapshot burst fraction and ectopic graded landscapes fit promoter on-rate modulation. Neither measures selectively varied native contact probability with direct live burst frequency; active tether chemistry, distance changes and synthetic context remain. The broad registered claim retains Γ, with causal engineered output acknowledged separately.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 8, 10, 15, 17, 18, 22, 33, 38, 39, 40, 45, 46, 47, 49, 51, 52, 55, 56, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Enhancers regulate genes, but continuous physical contact throughout every transcriptional burst is contradicted by native-locus measurements within their detection limits.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 35, 34, 45, 2, 7, 54 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Du M, Stitzinger SH, Spille JH et al. Direct observation of a condensate effect on super-enhancer controlled gene bursting. Cell. 2024.", "tier": "A", "kind": "primary", "pmid": "38194964", "doi": "10.1016/j.cell.2023.12.005", "url": "https://pubmed.ncbi.nlm.nih.gov/38194964/", "status_flags": [ "ErratumIn: PMID38614098" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38194964", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC3", "CSC4" ] }, { "n": 2, "citation": "Alexander JM, Guan J, Li B et al. Live-cell imaging reveals enhancer-dependent Sox2 transcription in the absence of enhancer proximity. eLife. 2019.", "tier": "A", "kind": "primary", "pmid": "31124784", "doi": "10.7554/eLife.41769", "url": "https://pubmed.ncbi.nlm.nih.gov/31124784/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31124784", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph20, 1:Results:paragraph42, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC3", "CH" ] }, { "n": 3, "citation": "Breda L, Motta I, Lourenco S et al. Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers. Blood. 2016.", "tier": "A", "kind": "primary", "pmid": "27405777", "doi": "10.1182/blood-2016-01-691089", "url": "https://pubmed.ncbi.nlm.nih.gov/27405777/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27405777", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2" ] }, { "n": 4, "citation": "Deng W, Rupon JW, Krivega I et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014.", "tier": "A", "kind": "primary", "pmid": "25126789", "doi": "10.1016/j.cell.2014.05.050", "url": "https://pubmed.ncbi.nlm.nih.gov/25126789/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25126789", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2" ] }, { "n": 5, "citation": "Peslak SA, Demirci S, Chandra V et al. Forced enhancer-promoter rewiring to alter gene expression in animal models. Molecular therapy. Nucleic acids. 2023.", "tier": "A", "kind": "primary", "pmid": "36852088", "doi": "10.1016/j.omtn.2023.01.016", "url": "https://pubmed.ncbi.nlm.nih.gov/36852088/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36852088", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC2" ] }, { "n": 6, "citation": "Krivega I, Dean A. LDB1-mediated enhancer looping can be established independent of mediator and cohesin. Nucleic acids research. 2017.", "tier": "A", "kind": "primary", "pmid": "28520978", "doi": "10.1093/nar/gkx433", "url": "https://pubmed.ncbi.nlm.nih.gov/28520978/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28520978", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2", "CSC3" ] }, { "n": 7, "citation": "Hsieh TS, Cattoglio C, Slobodyanyuk E et al. Enhancer-promoter interactions and transcription are largely maintained upon acute loss of CTCF, cohesin, WAPL or YY1. Nature genetics. 2022.", "tier": "A", "kind": "primary", "pmid": "36471071", "doi": "10.1038/s41588-022-01223-8", "url": "https://pubmed.ncbi.nlm.nih.gov/36471071/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36471071", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph21, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3", "CH" ] }, { "n": 8, "citation": "Narita T, Kilic S, Higashijima Y et al. Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation. Nature genetics. 2025.", "tier": "A", "kind": "primary", "pmid": "41254162", "doi": "10.1038/s41588-025-02404-x", "url": "https://pubmed.ncbi.nlm.nih.gov/41254162/", "status_flags": [ "ErratumIn: PMID41402458" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41254162", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph23, 1:Results:paragraph25, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC3", "CSC4" ] }, { "n": 9, "citation": "Zhang M, Huang H, Li J et al. ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry. Cell reports. 2024.", "tier": "A", "kind": "primary", "pmid": "38206813", "doi": "10.1016/j.celrep.2023.113663", "url": "https://pubmed.ncbi.nlm.nih.gov/38206813/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38206813", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3" ] }, { "n": 10, "citation": "Zuin J, Roth G, Zhan Y et al. Nonlinear control of transcription through enhancer-promoter interactions. Nature. 2022.", "tier": "A", "kind": "primary", "pmid": "35418676", "doi": "10.1038/s41586-022-04570-y", "url": "https://pubmed.ncbi.nlm.nih.gov/35418676/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35418676", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 2:Enhancer contacts modulate burst frequency:paragraph0, 2:Enhancer contacts modulate burst frequency:paragraph2. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC4" ] }, { "n": 11, "citation": "Bonev B, Mendelson Cohen N, Szabo Q et al. Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell. 2017.", "tier": "A", "kind": "primary", "pmid": "29053968", "doi": "10.1016/j.cell.2017.09.043", "url": "https://pubmed.ncbi.nlm.nih.gov/29053968/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29053968", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1" ] }, { "n": 12, "citation": "Weintraub AS, Li CH, Zamudio AV et al. YY1 Is a Structural Regulator of Enhancer-Promoter Loops. Cell. 2017.", "tier": "A", "kind": "primary", "pmid": "29224777", "doi": "10.1016/j.cell.2017.11.008", "url": "https://pubmed.ncbi.nlm.nih.gov/29224777/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29224777", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC1", "CSC3" ] }, { "n": 13, "citation": "Zhang F, Tanasa B, Merkurjev D et al. Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "tier": "A", "kind": "primary", "pmid": "25605944", "doi": "10.1073/pnas.1424228112", "url": "https://pubmed.ncbi.nlm.nih.gov/25605944/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25605944", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC3" ] }, { "n": 14, "citation": "Aboreden NG, Lam JC, Goel VY et al. LDB1 establishes multi-enhancer networks to regulate gene expression. Molecular cell. 2025.", "tier": "A", "kind": "primary", "pmid": "39721581", "doi": "10.1016/j.molcel.2024.11.037", "url": "https://pubmed.ncbi.nlm.nih.gov/39721581/", "status_flags": [ "UpdateOf: PMID39229045" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39721581", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC1", "CSC3" ] }, { "n": 15, "citation": "Calderon L, Weiss FD, Beagan JA et al. Cohesin-dependence of neuronal gene expression relates to chromatin loop length. eLife. 2022.", "tier": "A", "kind": "primary", "pmid": "35471149", "doi": "10.7554/eLife.76539", "url": "https://pubmed.ncbi.nlm.nih.gov/35471149/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35471149", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC3", "CSC4" ] }, { "n": 16, "citation": "Zhu Y, Balaji A, Han M et al. High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH. Cell. 2025.", "tier": "A", "kind": "primary", "pmid": "40239646", "doi": "10.1016/j.cell.2025.03.032", "url": "https://pubmed.ncbi.nlm.nih.gov/40239646/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40239646", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC1", "CSC3" ] }, { "n": 17, "citation": "Fukaya T, Lim B, Levine M. Enhancer Control of Transcriptional Bursting. Cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27293191", "doi": "10.1016/j.cell.2016.05.025", "url": "https://pubmed.ncbi.nlm.nih.gov/27293191/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27293191", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC4" ] }, { "n": 18, "citation": "Robles-Rebollo I, Cuartero S, Canellas-Socias A et al. Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters. Nature communications. 2022.", "tier": "A", "kind": "primary", "pmid": "35896525", "doi": "10.1038/s41467-022-31192-9", "url": "https://pubmed.ncbi.nlm.nih.gov/35896525/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35896525", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph21, 1:Results:paragraph22, 1:Results:paragraph26, 1:Results:paragraph27. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC3", "CSC4" ] }, { "n": 19, "citation": "Stumberger G, Hörl D, Tsouraki D et al. Nanoscale dynamics of enhancer-promoter interactions during exit from pluripotency. Nucleic acids research. 2025.", "tier": "A", "kind": "primary", "pmid": "41359380", "doi": "10.1093/nar/gkaf1255", "url": "https://pubmed.ncbi.nlm.nih.gov/41359380/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID41359380", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC1", "CSC3" ] }, { "n": 20, "citation": "Palacio M, Taatjes DJ. Real-time visualization of reconstituted transcription reveals RNAPII activation mechanisms at single promoters. Cell reports. 2025.", "tier": "A", "kind": "primary", "pmid": "40914943", "doi": "10.1016/j.celrep.2025.116251", "url": "https://pubmed.ncbi.nlm.nih.gov/40914943/", "status_flags": [ "UpdateOf: PMID39829877" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40914943", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC3" ] }, { "n": 21, "citation": "Ohishi H, Shinkai S, Owada H et al. Transcription-coupled changes in genomic region proximities during transcriptional bursting. Science advances. 2024.", "tier": "A", "kind": "primary", "pmid": "39642226", "doi": "10.1126/sciadv.adn0020", "url": "https://pubmed.ncbi.nlm.nih.gov/39642226/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39642226", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC1", "CSC3" ] }, { "n": 22, "citation": "Luo S, Wang Z, Zhang Z et al. Genome-wide inference reveals that feedback regulations constrain promoter-dependent transcriptional burst kinetics. Nucleic acids research. 2023.", "tier": "A", "kind": "primary", "pmid": "36583343", "doi": "10.1093/nar/gkac1204", "url": "https://pubmed.ncbi.nlm.nih.gov/36583343/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36583343", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC4" ] }, { "n": 24, "citation": "Lando D, Ma X, Cao Y et al. Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency. Molecular cell. 2024.", "tier": "A", "kind": "primary", "pmid": "38490199", "doi": "10.1016/j.molcel.2024.02.015", "url": "https://pubmed.ncbi.nlm.nih.gov/38490199/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38490199", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC1" ] }, { "n": 26, "citation": "Goel VY, Huseyin MK, Hansen AS. Region Capture Micro-C reveals coalescence of enhancers and promoters into nested microcompartments. Nature genetics. 2023.", "tier": "A", "kind": "primary", "pmid": "37157000", "doi": "10.1038/s41588-023-01391-1", "url": "https://pubmed.ncbi.nlm.nih.gov/37157000/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37157000", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC1", "CSC3" ] }, { "n": 27, "citation": "Lavagnolli T, Gupta P, Hörmanseder E et al. Initiation and maintenance of pluripotency gene expression in the absence of cohesin. Genes & development. 2015.", "tier": "A", "kind": "primary", "pmid": "25561493", "doi": "10.1101/gad.251835.114", "url": "https://pubmed.ncbi.nlm.nih.gov/25561493/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25561493", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC3" ] }, { "n": 28, "citation": "Sun F, Chronis C, Kronenberg M et al. Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods. Molecular cell. 2019.", "tier": "A", "kind": "primary", "pmid": "30527662", "doi": "10.1016/j.molcel.2018.10.039", "url": "https://pubmed.ncbi.nlm.nih.gov/30527662/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30527662", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC1", "CSC3" ] }, { "n": 29, "citation": "Apostolou E, Ferrari F, Walsh RM et al. Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. Cell stem cell. 2013.", "tier": "A", "kind": "primary", "pmid": "23665121", "doi": "10.1016/j.stem.2013.04.013", "url": "https://pubmed.ncbi.nlm.nih.gov/23665121/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23665121", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC1", "CSC3" ] }, { "n": 30, "citation": "Hsieh TS, Cattoglio C, Slobodyanyuk E et al. Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding. Molecular cell. 2020.", "tier": "A", "kind": "primary", "pmid": "32213323", "doi": "10.1016/j.molcel.2020.03.002", "url": "https://pubmed.ncbi.nlm.nih.gov/32213323/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32213323", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C28", "CSC1", "CSC3" ] }, { "n": 31, "citation": "Nora EP, Goloborodko A, Valton AL et al. Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell. 2017.", "tier": "A", "kind": "primary", "pmid": "28525758", "doi": "10.1016/j.cell.2017.05.004", "url": "https://pubmed.ncbi.nlm.nih.gov/28525758/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28525758", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C29", "CSC1", "CSC3" ] }, { "n": 32, "citation": "Hua P, Badat M, Hanssen LLP et al. Defining genome architecture at base-pair resolution. Nature. 2021.", "tier": "A", "kind": "primary", "pmid": "34108683", "doi": "10.1038/s41586-021-03639-4", "url": "https://pubmed.ncbi.nlm.nih.gov/34108683/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34108683", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C30", "CSC1" ] }, { "n": 33, "citation": "Luo R, Yan J, Oh JW et al. Dynamic network-guided CRISPRi screen identifies CTCF-loop-constrained nonlinear enhancer gene regulatory activity during cell state transitions. Nature genetics. 2023.", "tier": "A", "kind": "primary", "pmid": "37488417", "doi": "10.1038/s41588-023-01450-7", "url": "https://pubmed.ncbi.nlm.nih.gov/37488417/", "status_flags": [ "UpdateOf: PMID36945628" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37488417", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C31", "CSC3", "CSC4" ] }, { "n": 34, "citation": "Krivega I, Dale RK, Dean A. Role of LDB1 in the transition from chromatin looping to transcription activation. Genes & development. 2014.", "tier": "A", "kind": "primary", "pmid": "24874989", "doi": "10.1101/gad.239749.114", "url": "https://pubmed.ncbi.nlm.nih.gov/24874989/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24874989", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:Results:paragraph9, 0:Results:paragraph10, 0:Results:paragraph12, 0:Results:paragraph14. No complete-paper or supplement audit claimed.", "carries_claims": [ "C32", "CSC2", "CSC3", "CH" ] }, { "n": 35, "citation": "Deng W, Lee J, Wang H et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012.", "tier": "A", "kind": "primary", "pmid": "22682246", "doi": "10.1016/j.cell.2012.03.051", "url": "https://pubmed.ncbi.nlm.nih.gov/22682246/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID22682246", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph11. No complete-paper or supplement audit claimed.", "carries_claims": [ "C33", "CSC2", "CH" ] }, { "n": 36, "citation": "Lee J, Krivega I, Dale RK et al. The LDB1 Complex Co-opts CTCF for Erythroid Lineage-Specific Long-Range Enhancer Interactions. Cell reports. 2017.", "tier": "A", "kind": "primary", "pmid": "28636938", "doi": "10.1016/j.celrep.2017.05.072", "url": "https://pubmed.ncbi.nlm.nih.gov/28636938/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28636938", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C34", "CSC2", "CSC3" ] }, { "n": 37, "citation": "Benabdallah NS, Williamson I, Illingworth RS et al. Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation. Molecular cell. 2019.", "tier": "A", "kind": "primary", "pmid": "31494034", "doi": "10.1016/j.molcel.2019.07.038", "url": "https://pubmed.ncbi.nlm.nih.gov/31494034/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31494034", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph34. No complete-paper or supplement audit claimed.", "carries_claims": [ "C35", "CSC1", "CSC3" ] }, { "n": 38, "citation": "Symmons O, Pan L, Remeseiro S et al. The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances. Developmental cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27867070", "doi": "10.1016/j.devcel.2016.10.015", "url": "https://pubmed.ncbi.nlm.nih.gov/27867070/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27867070", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C36", "CSC3", "CSC4" ] }, { "n": 39, "citation": "Bower G, Hollingsworth EW, Jacinto SH et al. Range extender mediates long-distance enhancer activity. Nature. 2025.", "tier": "A", "kind": "primary", "pmid": "40604280", "doi": "10.1038/s41586-025-09221-6", "url": "https://pubmed.ncbi.nlm.nih.gov/40604280/", "status_flags": [ "UpdateOf: PMID38826394" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40604280", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C37", "CSC2", "CSC4" ] }, { "n": 40, "citation": "Paliou C, Guckelberger P, Schöpflin R et al. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "tier": "A", "kind": "primary", "pmid": "31147463", "doi": "10.1073/pnas.1900672116", "url": "https://pubmed.ncbi.nlm.nih.gov/31147463/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31147463", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C38", "CSC3", "CSC4" ] }, { "n": 41, "citation": "Williamson I, Kane L, Devenney PS et al. Developmentally regulated Shh expression is robust to TAD perturbations. Development (Cambridge, England). 2019.", "tier": "A", "kind": "primary", "pmid": "31511252", "doi": "10.1242/dev.179523", "url": "https://pubmed.ncbi.nlm.nih.gov/31511252/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31511252", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C39", "CSC3" ] }, { "n": 42, "citation": "Wu H, Zhang J, Tan L et al. Single-cell Micro-C profiles 3D genome structures at high resolution and characterizes multi-enhancer hubs. Nature genetics. 2025.", "tier": "A", "kind": "primary", "pmid": "40603633", "doi": "10.1038/s41588-025-02247-6", "url": "https://pubmed.ncbi.nlm.nih.gov/40603633/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40603633", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C40", "CSC1" ] }, { "n": 43, "citation": "Zhang S, Übelmesser N, Barbieri M et al. Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Nature genetics. 2023.", "tier": "A", "kind": "primary", "pmid": "37012454", "doi": "10.1038/s41588-023-01364-4", "url": "https://pubmed.ncbi.nlm.nih.gov/37012454/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37012454", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C41", "CSC1", "CSC3" ] }, { "n": 44, "citation": "Barshad G, Lewis JJ, Chivu AG et al. RNA polymerase II dynamics shape enhancer-promoter interactions. Nature genetics. 2023.", "tier": "A", "kind": "primary", "pmid": "37430091", "doi": "10.1038/s41588-023-01442-7", "url": "https://pubmed.ncbi.nlm.nih.gov/37430091/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37430091", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C42", "CSC1", "CSC3" ] }, { "n": 45, "citation": "Bartman CR, Hsu SC, Hsiung CC et al. Enhancer Regulation of Transcriptional Bursting Parameters Revealed by Forced Chromatin Looping. Molecular cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27067601", "doi": "10.1016/j.molcel.2016.03.007", "url": "https://pubmed.ncbi.nlm.nih.gov/27067601/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27067601", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph11, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "carries_claims": [ "C43", "CSC2", "CSC4", "CH" ] }, { "n": 46, "citation": "Jensen CL, Chen LF, Swigut T et al. Long-range regulation of transcription scales with genomic distance in a gene-specific manner. Molecular cell. 2025.", "tier": "A", "kind": "primary", "pmid": "39626660", "doi": "10.1016/j.molcel.2024.10.021", "url": "https://pubmed.ncbi.nlm.nih.gov/39626660/", "status_flags": [ "UpdateOf: PMID39071420" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39626660", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C44", "CSC4" ] }, { "n": 47, "citation": "Thomas HF, Feng S, Haslhofer F et al. Enhancer cooperativity can compensate for loss of activity over large genomic distances. Molecular cell. 2025.", "tier": "A", "kind": "primary", "pmid": "39626663", "doi": "10.1016/j.molcel.2024.11.008", "url": "https://pubmed.ncbi.nlm.nih.gov/39626663/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39626663", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C45", "CSC4" ] }, { "n": 48, "citation": "Reed KSM, Davis ES, Bond ML et al. Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription. Cell reports. 2022.", "tier": "A", "kind": "primary", "pmid": "36323252", "doi": "10.1016/j.celrep.2022.111567", "url": "https://pubmed.ncbi.nlm.nih.gov/36323252/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36323252", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C46", "CSC1", "CSC3" ] }, { "n": 49, "citation": "Kerschner JL, Meckler F, Coatti GC et al. The impact of genomic distance on enhancer-promoter interactions at the CFTR locus. Journal of cellular and molecular medicine. 2024.", "tier": "A", "kind": "primary", "pmid": "38372567", "doi": "10.1111/jcmm.18142", "url": "https://pubmed.ncbi.nlm.nih.gov/38372567/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38372567", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C47", "CSC3", "CSC4" ] }, { "n": 51, "citation": "Balasubramanian D, Borges Pinto P, Grasso A et al. Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries. Nucleic acids research. 2024.", "tier": "A", "kind": "primary", "pmid": "38084924", "doi": "10.1093/nar/gkad1183", "url": "https://pubmed.ncbi.nlm.nih.gov/38084924/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38084924", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C48", "CSC1", "CSC4" ] }, { "n": 52, "citation": "Tünnermann J, Roth G, Cramard J et al. Enhancer control of promoter activity and variability via frequency modulation of clustered transcriptional bursts. Nature genetics. 2026.", "tier": "A", "kind": "primary", "pmid": "42449150", "doi": "10.1038/s41588-026-02676-x", "url": "https://pubmed.ncbi.nlm.nih.gov/42449150/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42449150", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C49", "CSC4" ] }, { "n": 53, "citation": "Li J, Hsu A, Hua Y et al. Single-gene imaging links genome topology, promoter-enhancer communication and transcription control. Nature structural & molecular biology. 2020.", "tier": "A", "kind": "primary", "pmid": "32958948", "doi": "10.1038/s41594-020-0493-6", "url": "https://pubmed.ncbi.nlm.nih.gov/32958948/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32958948", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C50", "CSC1", "CSC3" ] }, { "n": 54, "citation": "Gómez Acuña LI, Flyamer I, Boyle S et al. Transcription decouples estrogen-dependent changes in enhancer-promoter contact frequencies and spatial proximity. PLoS genetics. 2024.", "tier": "A", "kind": "primary", "pmid": "38781242", "doi": "10.1371/journal.pgen.1011277", "url": "https://pubmed.ncbi.nlm.nih.gov/38781242/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38781242", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph9, 1:Results:paragraph12, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "carries_claims": [ "C51", "CSC1", "CSC3", "CH" ] }, { "n": 55, "citation": "Tei S, Bando M, Sakata T et al. Cohesin acts as a transcriptional gatekeeper by restraining pause-release to promote processive elongation. Nature communications. 2026.", "tier": "A", "kind": "primary", "pmid": "42637758", "doi": "10.1038/s41467-026-76738-3", "url": "https://pubmed.ncbi.nlm.nih.gov/42637758/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42637758", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC3", "CSC4" ] }, { "n": 56, "citation": "Rinzema NJ, Sofiadis K, Tjalsma SJD et al. Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes. Nature structural & molecular biology. 2022.", "tier": "A", "kind": "primary", "pmid": "35710842", "doi": "10.1038/s41594-022-00787-7", "url": "https://pubmed.ncbi.nlm.nih.gov/35710842/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35710842", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC2", "CSC4" ] }, { "n": 57, "citation": "Kubo N, Ishii H, Xiong X et al. Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation. Nature structural & molecular biology. 2021.", "tier": "A", "kind": "primary", "pmid": "33398174", "doi": "10.1038/s41594-020-00539-5", "url": "https://pubmed.ncbi.nlm.nih.gov/33398174/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33398174", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C54", "CSC2", "CSC3" ] }, { "n": 58, "citation": "Rao SSP, Huang SC, Glenn St Hilaire B et al. Cohesin Loss Eliminates All Loop Domains. Cell. 2017.", "tier": "A", "kind": "primary", "pmid": "28985562", "doi": "10.1016/j.cell.2017.09.026", "url": "https://pubmed.ncbi.nlm.nih.gov/28985562/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28985562", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC1", "CSC3" ] }, { "n": 59, "citation": "Bartman CR, Hamagami N, Keller CA et al. Transcriptional Burst Initiation and Polymerase Pause Release Are Key Control Points of Transcriptional Regulation. Molecular cell. 2019.", "tier": "A", "kind": "primary", "pmid": "30554946", "doi": "10.1016/j.molcel.2018.11.004", "url": "https://pubmed.ncbi.nlm.nih.gov/30554946/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30554946", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C56", "CSC3", "CSC4" ] }, { "n": 60, "citation": "Le DJ, Hafner A, Raja Venkatesh A et al. Single-cell 3D genome imaging shows super-enhancer hubs are rare, nonspecific, and neither necessary nor sufficient for transcriptional bursting. Cell genomics. 2026.", "tier": "A", "kind": "primary", "pmid": "42607687", "doi": "10.1016/j.xgen.2026.101331", "url": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42607687", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C57", "CSC1", "CSC3" ] } ], "independence_basis": { "required": false, "lines": [ { "label": "Native simultaneous geometry and output", "sources": [ 2 ], "excludes_error": "Same-cell measurements narrow population averaging but retain label/temporal-resolution failure modes." }, { "label": "Orthogonal native fixed assays", "sources": [ 37, 54 ], "excludes_error": "Different loci and contact-mapping/FISH designs reduce live-reporter-only error, but fixed averaging does not demonstrate zero transient contacts." }, { "label": "Protein-function separation", "sources": [ 34, 8, 18 ], "excludes_error": "Domain rescue and quiescent conditional perturbations narrow collapse/biochemistry alternatives; different multifunctional proteins do not independently establish one universal contact mechanism." } ], "shared_failure_mode_checked": true, "note": "Report count is not causal-line count. Distinct globin experiments keep distinct PMID study identifiers; shared tether chemistry is disclosed as a common failure class. Related synthetic landscape studies and baseline Micro-C reuse are not independent natural-mechanism validations. No positive qualifying SC3 causal lines cross the necessity threshold." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/enhancer-promoter-contact-transcription/OQMFd7VjTmK_DECg-Vyuqw/" ], "query_record_note": "Exact visible question/response retained privately in raw browser receipt.", "primary_comparison_count": 8, "primary_comparisons": [ { "pmid": "22682246", "doi": "10.1016/j.cell.2012.03.051", "source_type": "primary study report", "study_group": "PMID22682246", "access_depth": "full_text_partial", "consensus_aspect": "Engineered functional sufficiency, not natural continuous necessity", "result_comparison": "The original native-globin experiment supports activation by an active LDB1 tether with enhancer-dependent allele controls. Consensus correctly identifies a functional forced-looping result. The target gene is endogenous, but the recruited protein construct is synthetic; this does not prove geometry alone sufficient or contact continuously necessary.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/22682246/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-20-40-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\22682246-s1-p6-7-11.json" ] }, { "pmid": "27067601", "doi": "10.1016/j.molcel.2016.03.007", "source_type": "primary study report", "study_group": "PMID27067601", "access_depth": "full_text_partial", "consensus_aspect": "Burst fraction differs from live burst frequency", "result_comparison": "The original Results confirm increased snapshot burst fraction without increased burst size after forced contacts. The paper explicitly reserves definitive competing-contact dynamics for direct live imaging. Consensus's frequency language must therefore distinguish inferred likelihood from measured initiation frequency.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27067601/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-40-60-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\27067601-s1-p7-8-11-18.json" ] }, { "pmid": "31124784", "doi": "10.7554/eLife.41769", "source_type": "primary study report", "study_group": "PMID31124784", "access_depth": "full_text_partial", "consensus_aspect": "Sox2 spatial decoupling within measured resolution", "result_comparison": "The original same-cell imaging finds no contemporaneous or tested lag-window proximity relation to enhancer-dependent bursts. Original labels are offset by kilobases, and reporter delays and finite resolution leave brief or earlier contacts possible. The provider's initial categorical no-contact wording is too broad; its later targeted answer recognizes this limitation. Canonical original publication is 2019, despite provider 2018 labels.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/31124784/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-0-20-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\31124784-s1-p20-42-45-46-51-52.json" ] }, { "pmid": "31494034", "doi": "10.1016/j.molcel.2019.07.038", "source_type": "primary study report", "study_group": "PMID31494034", "access_depth": "full_text_partial", "consensus_aspect": "Neural Shh enhancers are not the limb ZRS", "result_comparison": "The original Results examine brain enhancers during neural differentiation and embryonic neural tissue. Activation increases measured separation, with a synthetic-loop positive imaging control. Consensus initially mislabels this as a limb-enhancer finding and cannot retrieve the exact paper in its targeted answer. The original body corrects the anatomy and preserves the fixed-assay limitation.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/31494034/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-20-40-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\31494034-s1-p9-10-12-34.json" ] }, { "pmid": "36471071", "doi": "10.1038/s41588-022-01223-8", "source_type": "primary study report", "study_group": "PMID36471071", "access_depth": "full_text_partial", "consensus_aspect": "Architectural loss retains most enhancer contacts", "result_comparison": "The original Results show approximately 80% of enhancer-promoter contacts remain unaltered after acute CTCF/cohesin depletion, while short-term gene changes are modest. This is an extrusion-factor maintenance test, not selective elimination of every productive contact. The targeted provider correctly cautions about retained contacts but did not validate this exact paper itself.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/36471071/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-0-20-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\36471071-s1-p8-17-21-25.json" ] }, { "pmid": "24874989", "doi": "10.1101/gad.239749.114", "source_type": "primary study report", "study_group": "PMID24874989", "access_depth": "full_text_partial", "consensus_aspect": "Correct original year and loop-competent mutant", "result_comparison": "The original 2014 paper restores globin looping with LDB1 DD4/5 deletion without restoring transcription or polymerase recruitment. Consensus's exact-paper search failed and relied on 2013-labeled title surrogates. The original result separates looping from downstream activation chemistry; it does not prove all contacts unnecessary.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/24874989/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-20-40-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\24874989-s0-p9-10-12-14.json" ] }, { "pmid": "35418676", "doi": "10.1038/s41586-022-04570-y", "source_type": "primary study report", "study_group": "PMID35418676", "access_depth": "full_text_partial", "consensus_aspect": "The 2022 graded landscape is a distinct publication", "result_comparison": "The original 2022 study uses an ectopic regulatory landscape and largely founder-line contact probabilities to fit nonlinear promoter on-rate behavior. It is distinct from the 2026 live burst-cluster paper. Consensus's conditional conflation of the papers is corrected; neither proves universal continuous native-locus contact necessity.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35418676/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-0-20-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\35418676-s2-p0-2.json" ] }, { "pmid": "35896525", "doi": "10.1038/s41467-022-31192-9", "source_type": "primary study report", "study_group": "PMID35896525", "access_depth": "full_text_partial", "consensus_aspect": "Conditional macrophage deletion is not acute degradation", "result_comparison": "The original Methods/Results use conditional Rad21 deletion in quiescent macrophages, with cell-cycle and damage checks. Burst participation is uncoupled despite similar measured enhancer-promoter distances at several loci. Consensus called this acute degradation; the original experiment corrects the intervention identity and retains resolution limitations.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35896525/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\examinations\\original-0-20-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\body-presentation-receipts\\35896525-s1-p9-21-22-26-27.json" ] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\enhancer-promoter-looping\\consensus-browser-2026-10-12.json", "sha256": "d0bd3fe67d4150f6d2cdf21c99a04451d929b9093434d441cebd6f66471aebfc" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T19:55:27.278692+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }