{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "3D Genome Folding as Regulatory Determinant", "entry_form": "phenomenon", "gradeable_restatement": "Three-dimensional genome folding is a primary causal determinant of transcriptional regulation across mammalian loci.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Mammalian lineage, locus, architectural mode and activation/maintenance phase specified before expression response; fly studies remain comparative evidence", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "3D Genome Folding as Regulatory Determinant", "central_claim": "Three-dimensional genome folding is a primary causal determinant of transcriptional regulation across mammalian loci.", "proposed_mechanism": "Three-dimensional genome folding is a primary causal determinant of transcriptional regulation across mammalian loci.", "claimed_scope": "Three-dimensional genome folding is a primary causal determinant of transcriptional regulation across mammalian loci.", "claimed_level": [ "response", "maintenance" ], "is_conjunctive": true, "conjunctive_note": "Topology existence and locus-specific function are scored separately from broad regulatory primacy. Defined baseline loci and folding features, not loci selected for a positive expression response, establish scope. Global architectural-protein depletion does not isolate topology from protein biochemical activity." }, "rubric_routing": { "primary_rubric": "03-epigenetics-gene-regulation.md", "secondary_rubrics": [], "index_notes_applied": [ "Topology existence and locus-specific function are scored separately from broad regulatory primacy. Defined baseline loci and folding features, not loci selected for a positive expression response, establish scope. Global architectural-protein depletion does not isolate topology from protein biochemical activity." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Loops, domains and compartments are reproducible genome features.", "subclaim_type": "existence", "scope": "cell state, assay and contact scale", "claimed_scope": "cell state, assay and contact scale", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Orthogonal contact and imaging measurements", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Independent contact maps, fixed-cell tracing and live-cell controls reproducibly reveal dynamic loops, domains and compartments. Β reflects the noncausal existence formulation; physical formation mechanisms have direct perturbational support but do not transfer to transcriptional primacy." }, { "id": "SC2", "statement": "Specific folding features causally regulate transcription at defined loci.", "subclaim_type": "mechanism", "scope": "locus and architectural feature defined before expression response", "claimed_scope": "locus and architectural feature defined before expression response", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Local topology perturbation and matched restoration", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human structural variants recreated in mice, boundary-preserving controls, CTCF motif inversions and enhancer-dependent directed globin activation converge on causal contribution at defined endogenous loci. They fail differently; separation-of-function LDB1 controls show that contacts also require competent biochemistry. Ζ applies to specific architectural contributions, not universal necessity or contact sufficiency." }, { "id": "SC3", "statement": "Folding is a primary regulatory determinant across mammalian loci.", "subclaim_type": "primacy", "scope": "prespecified lineages, activation and maintenance phases, and representative loci", "claimed_scope": "prespecified lineages, activation and maintenance phases, and representative loci", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Paired topology/biochemical perturbations with nascent transcription and rescue", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Short-term nascent transcription and many fine enhancer-promoter contacts persist after loop-extrusion factor loss; large endogenous edits are often buffered. Positive local and activation-context effects do not establish broad rate-limiting primacy. Protein chemistry, activation/maintenance timing and compartment modes prevent a global topology-only inference." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Topology existence and locus-specific function are scored separately from broad regulatory primacy. Defined baseline loci and folding features, not loci selected for a positive expression response, establish scope. Global architectural-protein depletion does not isolate topology from protein biochemical activity.", "primary_subclaim_id": "SC3", "aggregation_derivation": "The preregistered scope-matched gate is SC3, yielding Γ. SC2 reaches Ζ through independent endogenous boundary edits, allele-resolved human/mouse developmental tests and locus-directed functional rescue, interpreted as architectural contribution rather than a sole switch. SC1 is an existence statement: Β records robust structural observation without pretending existence itself proves regulatory causality. Its empirical reality is well established and is not refuted by this causal ladder.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Transition-dependent architecture with maintenance redundancy", "core_claim": "Architecture facilitates particular activation transitions while established output can persist.", "explains_what_nominal_does_not": "Architecture facilitates particular activation transitions while established output can persist.", "strongest_supporting_evidence": [ "Distant Shh activation, neuronal gene classes and promoter CTCF rescue support restricted necessity (36097291,35471149,33398174)." ], "strongest_contradictory_evidence": [ "Not all immediate-early activation requires cohesin; protein chemistry remains intertwined." ], "hsef_level_for_this_model": "Ε", "rationale": "Distant Shh activation, neuronal gene classes and promoter CTCF rescue support restricted necessity (36097291,35471149,33398174). Not all immediate-early activation requires cohesin; protein chemistry remains intertwined." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Permissive enhancer access with biochemical compatibility", "core_claim": "Architecture shapes opportunities and insulation, while competent enhancer/promoter biochemistry determines output.", "explains_what_nominal_does_not": "Architecture shapes opportunities and insulation, while competent enhancer/promoter biochemistry determines output.", "strongest_supporting_evidence": [ "Boundary-preserving developmental controls and LDB1 looping/activation separation (25959774,24874989)." ], "strongest_contradictory_evidence": [ "Forced native globin activation and selected boundary edits show architecture can exert stronger instructive effects (22682246,38452764)." ], "hsef_level_for_this_model": "Ε", "rationale": "Boundary-preserving developmental controls and LDB1 looping/activation separation (25959774,24874989). Forced native globin activation and selected boundary edits show architecture can exert stronger instructive effects (22682246,38452764)." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Transcription-first architectural remodeling", "core_claim": "Transcription can generate or alter fine chromatin features, creating reciprocal causality.", "explains_what_nominal_does_not": "Transcription can generate or alter fine chromatin features, creating reciprocal causality.", "strongest_supporting_evidence": [ "Transcription inhibition disrupts fine Micro-C features and temporal maps show reciprocal dynamics (32213323,36323252)." ], "strongest_contradictory_evidence": [ "Many higher structures and microcompartments persist without transcription; drugs have indirect effects (37157000)." ], "hsef_level_for_this_model": "Δ", "rationale": "Transcription inhibition disrupts fine Micro-C features and temporal maps show reciprocal dynamics (32213323,36323252). Many higher structures and microcompartments persist without transcription; drugs have indirect effects (37157000)." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Affinity-driven compartmentalization", "core_claim": "Compatible chromatin states and regulatory factors coalesce independently of loop extrusion.", "explains_what_nominal_does_not": "Compatible chromatin states and regulatory factors coalesce independently of loop extrusion.", "strongest_supporting_evidence": [ "Polycomb contacts and nested microcompartments persist after cohesin loss (31968256,37157000)." ], "strongest_contradictory_evidence": [ "A contact pattern is not by itself proof of thermodynamic phase separation or global transcriptional mechanism." ], "hsef_level_for_this_model": "Γ", "rationale": "Polycomb contacts and nested microcompartments persist after cohesin loss (31968256,37157000). A contact pattern is not by itself proof of thermodynamic phase separation or global transcriptional mechanism." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Topological primary switch", "core_claim": "Folding broadly initiates and rate-limits mammalian transcription.", "explains_what_nominal_does_not": "Folding broadly initiates and rate-limits mammalian transcription.", "strongest_supporting_evidence": [ "Local boundary pathology and forced globin activation are its strongest original cases (25959774,22682246)." ], "strongest_contradictory_evidence": [ "Maintained nascent output and looping-intact inactive globin challenge broad sufficiency/necessity (36471071,24874989)." ], "hsef_level_for_this_model": "Γ", "rationale": "Local boundary pathology and forced globin activation are its strongest original cases (25959774,22682246). Maintained nascent output and looping-intact inactive globin challenge broad sufficiency/necessity (36471071,24874989)." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. During a defined transition, orthogonally restore native topology while retaining a biochemical-deficient factor, and restore factor chemistry while blocking topology. Paired nascent output, live distance and activation-history readouts would distinguish instructive topology from permissive access and molecular memory.", "study_separating_rank1_from_rank2": "During a defined transition, orthogonally restore native topology while retaining a biochemical-deficient factor, and restore factor chemistry while blocking topology. Paired nascent output, live distance and activation-history readouts would distinguish instructive topology from permissive access and molecular memory.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39721581", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "murine erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Acute LDB1 loss and engineered recruitment alter multi-enhancer networks; many connections persist without CTCF/cohesin/YY1.", "what_it_does_not_show": "LDB1 transcriptional biochemistry and contact changes are intertwined; one lineage does not establish genome-wide primacy. Updates preprint 39229045.", "confounders_present": [ "LDB1 transcriptional biochemistry and contact changes are intertwined; one lineage does not establish genome-wide primacy. Updates preprint 39229045." ], "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": [] }, "shared_components": [ "UpdateOf 39229045 preprint, not counted separately." ] }, { "n": 2, "pmid": "36097291", "title": "Cohesin is required for long-range enhancer action at the Shh locus.", "citation": "Kane L, Williamson I, Flyamer IM et al. Cohesin is required for long-range enhancer action at the Shh locus. Nature structural & molecular biology. 2022.", "doi": "10.1038/s41594-022-00821-8", "pmcid": "PMC7613721", "url": "https://pubmed.ncbi.nlm.nih.gov/36097291/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36097291/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36097291", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cohesin is required for synthetic activation from distant Shh enhancers, while promoter and proximal activation remain independent.", "what_it_does_not_show": "Artificial activation and acute protein loss do not isolate topology from all protein functions; distance and context constrain necessity.", "confounders_present": [ "Artificial activation and acute protein loss do not isolate topology from all protein functions; distance and context constrain 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": [] }, "shared_components": [ "Synthetic Shh activation and related ESC degron platforms; shares factors with earlier architectural depletion work." ] }, { "n": 3, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36471071", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph20, 1:Results:paragraph25, 1:Results:paragraph31, 1:Results:paragraph47, 3:Methods:paragraph0, 3:Methods:paragraph39. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Most enhancer-promoter interactions and nascent transcription remain after three-hour CTCF/cohesin/WAPL/YY1 depletion.", "what_it_does_not_show": "Short-term maintenance is tested; activation and later effects remain open. Cohesin affects transcription-factor binding.", "confounders_present": [ "Short-term maintenance is tested; activation and later effects remain open. Cohesin affects transcription-factor binding." ], "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": [] }, "shared_components": [] }, { "n": 4, "pmid": "32572210", "title": "Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes.", "citation": "Luppino JM, Park DS, Nguyen SC et al. Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes. Nature genetics. 2020.", "doi": "10.1038/s41588-020-0647-9", "pmcid": "PMC7416539", "url": "https://pubmed.ncbi.nlm.nih.gov/32572210/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32572210/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32572210", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Imaging shows stochastic domain intermingling; cohesin loss reduces contacts, whereas CTCF/WAPL loss increases cohesin-dependent mixing and alters boundary-proximal bursting.", "what_it_does_not_show": "Population TAD loss does not imply increased single-cell ectopic contact; protein depletion has biochemical effects.", "confounders_present": [ "Population TAD loss does not imply increased single-cell ectopic contact; protein depletion has biochemical effects." ], "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": [] }, "shared_components": [] }, { "n": 5, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28525758", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Dose-dependent CTCF depletion and restoration change domain insulation; compartments persist and nondividing cells need CTCF for insulation.", "what_it_does_not_show": "Physical insulation recovers but most expression changes do not fully reset after washout; early downregulated promoters show direct CTCF binding. Late viability and direct protein functions constrain topology attribution.", "confounders_present": [ "Physical insulation recovers but most expression changes do not fully reset after washout; early downregulated promoters show direct CTCF binding. Late viability and direct protein functions constrain topology 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": [] }, "shared_components": [] }, { "n": 6, "pmid": "34002095", "title": "CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains.", "citation": "Huang H, Zhu Q, Jussila A et al. CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains. Nature genetics. 2021.", "doi": "10.1038/s41588-021-00863-6", "pmcid": "PMC8853952", "url": "https://pubmed.ncbi.nlm.nih.gov/34002095/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34002095/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34002095", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse stem-cell reporter assay", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Tandem CTCF sites and sequence context provide insulation and weaken local contacts.", "what_it_does_not_show": "Reporter insulation and DNA/protein binding effects cannot establish endogenous transcriptional primacy.", "confounders_present": [ "Reporter insulation and DNA/protein binding effects cannot establish endogenous transcriptional primacy." ], "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": [] }, "shared_components": [] }, { "n": 7, "pmid": "34585664", "title": "3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression.", "citation": "Himadewi P, Wang XQD, Feng F et al. 3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression. eLife. 2021.", "doi": "10.7554/eLife.70557", "pmcid": "PMC8500713", "url": "https://pubmed.ncbi.nlm.nih.gov/34585664/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34585664/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34585664", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human erythroid cells and primary CD34-positive cells", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates.", "what_it_does_not_show": "Endogenous locus evidence; motif orientation and protein recruitment are linked. No patient clinical outcome or broad primacy test.", "confounders_present": [ "Endogenous locus evidence; motif orientation and protein recruitment are linked. No patient clinical outcome or broad primacy test." ], "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": [] }, "shared_components": [] }, { "n": 8, "pmid": "33512425", "title": "Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis.", "citation": "Qi Q, Cheng L, Tang X et al. Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis. Blood. 2021.", "doi": "10.1182/blood.2020005780", "pmcid": "PMC7955410", "url": "https://pubmed.ncbi.nlm.nih.gov/33512425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33512425/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33512425", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "primary human blood and erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Lineage-specific CTCF binding and motif deletion at RBM38 alter enhancer interaction and erythropoiesis.", "what_it_does_not_show": "One endogenous locus and regulatory DNA edit; topology-only attribution and exact scope need controls.", "confounders_present": [ "One endogenous locus and regulatory DNA edit; topology-only attribution and exact scope need controls." ], "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": [] }, "shared_components": [] }, { "n": 9, "pmid": "34429148", "title": "Acute depletion of CTCF rewires genome-wide chromatin accessibility.", "citation": "Xu B, Wang H, Wright S et al. Acute depletion of CTCF rewires genome-wide chromatin accessibility. Genome biology. 2021.", "doi": "10.1186/s13059-021-02466-0", "pmcid": "PMC8386078", "url": "https://pubmed.ncbi.nlm.nih.gov/34429148/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34429148/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34429148", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Acute CTCF loss alters accessibility near binding sites and selected gene output without a large global transcriptional change.", "what_it_does_not_show": "Accessibility, CTCF partners and contact changes cannot by themselves separate direct biochemical regulation from topology.", "confounders_present": [ "Accessibility, CTCF partners and contact changes cannot by themselves separate direct biochemical regulation from topology." ], "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": [] }, "shared_components": [] }, { "n": 10, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35471149", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "primary mouse cortical neurons", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Immediate-early activation and short Fos contacts persist without cohesin; longer-loop secondary response and synapse genes show greater dependence.", "what_it_does_not_show": "Dependence is gene-class and distance specific; chronic developmental and direct protein effects remain alternative causes.", "confounders_present": [ "Dependence is gene-class and distance specific; chronic developmental and direct protein effects remain alternative causes." ], "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": [] }, "shared_components": [] }, { "n": 11, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36323252", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "activated macrophages", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Eight-timepoint maps associate enhancer acetylation, expression and loop changes with reciprocal timing.", "what_it_does_not_show": "Temporal associations do not isolate causality; transcription itself can impede loops.", "confounders_present": [ "Temporal associations do not isolate causality; transcription itself can impede loops." ], "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": [] }, "shared_components": [] }, { "n": 12, "pmid": "38509385", "title": "Increased enhancer-promoter interactions during developmental enhancer activation in mammals.", "citation": "Chen Z, Snetkova V, Bower G et al. Increased enhancer-promoter interactions during developmental enhancer activation in mammals. Nature genetics. 2024.", "doi": "10.1038/s41588-024-01681-2", "pmcid": "PMC11203181", "url": "https://pubmed.ncbi.nlm.nih.gov/38509385/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38509385/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38509385", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "mouse embryonic tissues", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Nearly a thousand developmental enhancers show moderate tissue-specific increases in contacts; stable contacts can persist without enhancer.", "what_it_does_not_show": "Activity-contact correlation and enhancer absence do not demonstrate broad topology necessity.", "confounders_present": [ "Activity-contact correlation and enhancer absence do not demonstrate broad topology 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": [] }, "shared_components": [] }, { "n": 13, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35418676", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Enhancer action depends on genomic distance:paragraph0, 1:Enhancer action depends on genomic distance:paragraph2, 1:Enhancer action depends on genomic distance:paragraph3, 1:Enhancer action depends on genomic distance:paragraph4, 2:Enhancer contacts modulate burst frequency:paragraph0, 2:Enhancer contacts modulate burst frequency:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "engineered mammalian reporter cell lines", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Dense enhancer repositioning reveals nonlinear relationships between contact probability, enhancer strength and promoter output.", "what_it_does_not_show": "Engineered eGFP/Sox2-SCR transgene in a neutral TAD with internal CTCF sites removed; founder contact maps infer probabilities. Nonlinear model fit is not direct observation of momentary endogenous contact-to-burst causality.", "confounders_present": [ "Engineered eGFP/Sox2-SCR transgene in a neutral TAD with internal CTCF sites removed; founder contact maps infer probabilities. Nonlinear model fit is not direct observation of momentary endogenous contact-to-burst 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": [] }, "shared_components": [] }, { "n": 14, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33398174", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse stem-cell neural differentiation", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Promoter CTCF binding loss decreases selected distant contacts and expression; tethered CTCF restores both.", "what_it_does_not_show": "CTCF tethering restores biochemical activities too; adult-tissue breadth is correlational.", "confounders_present": [ "CTCF tethering restores biochemical activities too; adult-tissue breadth is correlational." ], "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": [] }, "shared_components": [] }, { "n": 15, "pmid": "38467791", "title": "Enhancer-promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation.", "citation": "Pollex T, Rabinowitz A, Gambetta MC et al. Enhancer-promoter interactions become more instructive in the transition from cell-fate specification to tissue differentiation. Nature genetics. 2024.", "doi": "10.1038/s41588-024-01678-x", "pmcid": "PMC11018526", "url": "https://pubmed.ncbi.nlm.nih.gov/38467791/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38467791/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38467791", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "Drosophila embryonic cell lineages", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Enhancer-promoter topology is permissive at specification and better correlates with activity during terminal differentiation.", "what_it_does_not_show": "Outside registered mammalian scope; contact/activity observations do not prove necessity.", "confounders_present": [ "Outside registered mammalian scope; contact/activity observations do not prove 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": [] }, "shared_components": [] }, { "n": 16, "pmid": "33431820", "title": "BET inhibition disrupts transcription but retains enhancer-promoter contact.", "citation": "Crump NT, Ballabio E, Godfrey L et al. BET inhibition disrupts transcription but retains enhancer-promoter contact. Nature communications. 2021.", "doi": "10.1038/s41467-020-20400-z", "pmcid": "PMC7801379", "url": "https://pubmed.ncbi.nlm.nih.gov/33431820/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33431820/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33431820", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "BET inhibition and BRD4 loss reduce transcription while enhancer-promoter contacts persist.", "what_it_does_not_show": "Protein and solvent interventions are not phase-state specific; contact persistence need not exclude transient interactions.", "confounders_present": [ "Protein and solvent interventions are not phase-state specific; contact persistence need not exclude transient interactions." ], "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": [] }, "shared_components": [] }, { "n": 17, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31494034", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse stem-cell neural differentiation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Shh activation accompanies decreased spatial enhancer proximity; synthetic activation reproduces it with PARP dependence.", "what_it_does_not_show": "One locus; fixed-cell distance and ligation contact differ; contact events below resolution may remain.", "confounders_present": [ "One locus; fixed-cell distance and ligation contact differ; contact events below resolution may 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": [] }, "shared_components": [] }, { "n": 18, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32958948", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Live imaging resolves regulatory-factor clustering and frequent enhancer-gene proximity within nanoenvironments.", "what_it_does_not_show": "Physical proximity and recruitment do not isolate topology as the initiating causal variable.", "confounders_present": [ "Physical proximity and recruitment do not isolate topology as the initiating causal variable." ], "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": [] }, "shared_components": [] }, { "n": 19, "pmid": "36449519", "title": "Co-depletion of NIPBL and WAPL balance cohesin activity to correct gene misexpression.", "citation": "Luppino JM, Field A, Nguyen SC et al. Co-depletion of NIPBL and WAPL balance cohesin activity to correct gene misexpression. PLoS genetics. 2022.", "doi": "10.1371/journal.pgen.1010528", "pmcid": "PMC9744307", "url": "https://pubmed.ncbi.nlm.nih.gov/36449519/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36449519/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36449519", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human HCT116 cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NIPBL or WAPL depletion each misregulates roughly two thousand genes; co-depletion restores most misexpression.", "what_it_does_not_show": "Compensatory protein perturbation supports cohesin balance but cannot exclude non-topological biochemical functions.", "confounders_present": [ "Compensatory protein perturbation supports cohesin balance but cannot exclude non-topological biochemical functions." ], "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": [] }, "shared_components": [] }, { "n": 20, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28520978", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "TATA deletion preserves looping despite transcription loss; activation-deficient LDB1 restores contact without Mediator/cohesin.", "what_it_does_not_show": "Looping sufficiency is explicitly limited; linked biochemical functions require separation.", "confounders_present": [ "Looping sufficiency is explicitly limited; linked biochemical functions require separation." ], "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": [] }, "shared_components": [] }, { "n": 21, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24874989", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph9, 0:Results:paragraph12, 0:Results:paragraph14, 0:Results:paragraph24. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "erythroid cells", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "LDB1 DD4/5 mutant preserves dimerization and looping but lacks transcriptional activation and coregulator recruitment.", "what_it_does_not_show": "Matched separation at one locus constrains a loop-only explanation; mutation has identified biochemical consequences.", "confounders_present": [ "Matched separation at one locus constrains a loop-only explanation; mutation has identified biochemical consequences." ], "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": [] }, "shared_components": [] }, { "n": 22, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Globin-LDB1-tethering-bursting", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Forced globin contact increases burst fraction, with little burst-size effect.", "what_it_does_not_show": "Related LDB1 platform and locus; forced protein recruitment is not topology-only manipulation.", "confounders_present": [ "Related LDB1 platform and locus; forced protein recruitment is not topology-only manipulation." ], "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": [] }, "shared_components": [ "Related globin/LDB1 tethering platform; not a separate assay-class confirmation." ] }, { "n": 23, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Globin-LDB1-tethering-2012", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "GATA1-null mouse erythroblasts", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LDB1 tethering reactivates native beta-globin, requiring the distant LCR.", "what_it_does_not_show": "Artificial tethering in a deficient background can restore cofactor functions; locus requirement cannot establish universal primacy.", "confounders_present": [ "Artificial tethering in a deficient background can restore cofactor functions; locus requirement cannot establish universal primacy." ], "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": [] }, "shared_components": [] }, { "n": 24, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Globin-LDB1-tethering-2014", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse and primary adult human erythroblasts", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Forced LDB1 recruitment reactivates developmentally silenced globins and changes LCR contacts.", "what_it_does_not_show": "Same tethering family; high output in culture is not clinical efficacy or general topology sufficiency.", "confounders_present": [ "Same tethering family; high output in culture is not clinical efficacy or general topology sufficiency." ], "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": [] }, "shared_components": [ "Same LDB1/zinc-finger globin recruitment paradigm as 22682246; distinct report, shared mechanistic failure mode." ] }, { "n": 25, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Globin-LDB1-sickle-ex-vivo", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "patient-derived sickle erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ZF-LDB1 raises fetal haemoglobin and reduces hypoxic sickling compared with selected drug regimens.", "what_it_does_not_show": "Ex vivo gene delivery; related globin programme; in vivo safety and broad transcriptional role untested.", "confounders_present": [ "Ex vivo gene delivery; related globin programme; in vivo safety and broad transcriptional role 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": [] }, "shared_components": [ "Related zinc-finger LDB1 globin programme; patient-derived cells extend context, not a clinical trial." ] }, { "n": 26, "pmid": "38452764", "title": "Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.", "citation": "Kim KL, Rahme GJ, Goel VY et al. Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation. Molecular cell. 2024.", "doi": "10.1016/j.molcel.2024.02.007", "pmcid": "PMC10997458", "url": "https://pubmed.ncbi.nlm.nih.gov/38452764/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38452764/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38452764", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human GIST regulatory landscape", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction.", "what_it_does_not_show": "Regulatory DNA/protein changes accompany topology; tumour association differs from autonomous initiation.", "confounders_present": [ "Regulatory DNA/protein changes accompany topology; tumour association differs from autonomous initiation." ], "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": [] }, "shared_components": [] }, { "n": 27, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32213323", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Micro-C resolves fine enhancer/promoter structures; acute transcription inhibition disrupts fine features but not higher architecture.", "what_it_does_not_show": "Intervention supports reverse causality as well as coupling; drugs are pleiotropic.", "confounders_present": [ "Intervention supports reverse causality as well as coupling; drugs are pleiotropic." ], "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": [] }, "shared_components": [] }, { "n": 28, "pmid": "31968256", "title": "Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells.", "citation": "Rhodes JDP, Feldmann A, Hernández-Rodríguez B et al. Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells. Cell reports. 2020.", "doi": "10.1016/j.celrep.2019.12.057", "pmcid": "PMC6988126", "url": "https://pubmed.ncbi.nlm.nih.gov/31968256/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31968256/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31968256", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cohesin loss removes TADs while PRC1-dependent contacts persist or strengthen and repression changes.", "what_it_does_not_show": "Distinct architectural modes and direct PRC1 biochemical repression prevent universal loop-extrusion attribution.", "confounders_present": [ "Distinct architectural modes and direct PRC1 biochemical repression prevent universal loop-extrusion 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": [] }, "shared_components": [] }, { "n": 29, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31511252", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse development", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Multiple Shh TAD/boundary edits leave expression and phenotype largely intact; one larger deletion affects neighboring Mnx1.", "what_it_does_not_show": "Endogenous negative test; buffering, locus choice and larger-edit regulatory content limit generalization.", "confounders_present": [ "Endogenous negative test; buffering, locus choice and larger-edit regulatory content limit generalization." ], "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": [] }, "shared_components": [] }, { "n": 30, "pmid": "35420890", "title": "Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.", "citation": "Gabriele M, Brandão HB, Grosse-Holz S et al. Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging. Science (New York, N.Y.). 2022.", "doi": "10.1126/science.abn6583", "pmcid": "PMC9069445", "url": "https://pubmed.ncbi.nlm.nih.gov/35420890/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35420890/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35420890", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph9, 1:Main text:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "live mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Fbn2 boundary loops are rare and dynamic, with roughly 3–6.5 percent occupancy and 10–30-minute lifetimes.", "what_it_does_not_show": "One locus and Bayesian state inference; population loops do not mean permanent structures in every cell.", "confounders_present": [ "One locus and Bayesian state inference; population loops do not mean permanent structures in every cell." ], "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": [] }, "shared_components": [ "CTCF/cohesin/WAPL degron and Micro-C platforms overlap Hsieh programme; imaging has different localization/inference errors." ] }, { "n": 31, "pmid": "30361340", "title": "Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells.", "citation": "Bintu B, Mateo LJ, Su JH et al. Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aau1783", "pmcid": "PMC6535145", "url": "https://pubmed.ncbi.nlm.nih.gov/30361340/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30361340/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30361340", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "single mammalian cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Chromatin tracing detects heterogeneous TAD-like conformations; cohesin loss removes preferred boundary positions but not single-cell domains.", "what_it_does_not_show": "Population-domain loss differs from absence of local conformations; fixed imaging is not transcriptional causal proof.", "confounders_present": [ "Population-domain loss differs from absence of local conformations; fixed imaging is not transcriptional causal 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": [] }, "shared_components": [] }, { "n": 32, "pmid": "29217591", "title": "Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins.", "citation": "Wutz G, Várnai C, Nagasaka K et al. Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins. The EMBO journal. 2017.", "doi": "10.15252/embj.201798004", "pmcid": "PMC5730888", "url": "https://pubmed.ncbi.nlm.nih.gov/29217591/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29217591/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29217591", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cohesin, CTCF, WAPL and PDS5 perturbations change domains, boundaries and loop lengths differently.", "what_it_does_not_show": "Protein effects establish structural control, not necessarily broad transcriptional initiation.", "confounders_present": [ "Protein effects establish structural control, not necessarily broad transcriptional initiation." ], "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": [] }, "shared_components": [] }, { "n": 33, "pmid": "31308546", "title": "Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression.", "citation": "Ghavi-Helm Y, Jankowski A, Meiers S et al. Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nature genetics. 2019.", "doi": "10.1038/s41588-019-0462-3", "pmcid": "PMC7116017", "url": "https://pubmed.ncbi.nlm.nih.gov/31308546/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31308546/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31308546", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "Drosophila embryos", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Allele-specific balancer rearrangements disrupt many contacts while most expression remains stable.", "what_it_does_not_show": "Outside mammalian scope; developmental compensation and complex rearrangements remain.", "confounders_present": [ "Outside mammalian scope; developmental compensation and complex rearrangements 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": [] }, "shared_components": [] }, { "n": 34, "pmid": "30742094", "title": "Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations.", "citation": "Kraft K, Magg A, Heinrich V et al. Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nature cell biology. 2019.", "doi": "10.1038/s41556-019-0273-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30742094/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30742094/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30742094", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse limb development", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype.", "what_it_does_not_show": "Endogenous functional test with rescue; selected enhancer-rich landscape and regulatory-sequence effects limit breadth.", "confounders_present": [ "Endogenous functional test with rescue; selected enhancer-rich landscape and regulatory-sequence effects limit breadth." ], "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": [] }, "shared_components": [] }, { "n": 35, "pmid": "34197738", "title": "Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression.", "citation": "Vos ESM, Valdes-Quezada C, Huang Y et al. Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression. Molecular cell. 2021.", "doi": "10.1016/j.molcel.2021.06.008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34197738/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34197738/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34197738", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Allelic boundary edits at Prdm14 change extrusion trajectories; activation can cross a prominent boundary and need not require paused looping.", "what_it_does_not_show": "Context-specific endogenous edits separate simplistic boundary loops; enhancer activity contributes to architecture.", "confounders_present": [ "Context-specific endogenous edits separate simplistic boundary loops; enhancer activity contributes to architecture." ], "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": [] }, "shared_components": [] }, { "n": 36, "pmid": "26276636", "title": "CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function.", "citation": "Guo Y, Xu Q, Canzio D et al. CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function. Cell. 2015.", "doi": "10.1016/j.cell.2015.07.038", "pmcid": "PMC4642453", "url": "https://pubmed.ncbi.nlm.nih.gov/26276636/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26276636/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26276636", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian protocadherin and globin loci", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity.", "what_it_does_not_show": "Local motif orientation preserves some sequence content but changes protein geometry; limited loci.", "confounders_present": [ "Local motif orientation preserves some sequence content but changes protein geometry; limited loci." ], "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": [] }, "shared_components": [] }, { "n": 37, "pmid": "35502750", "title": "Inversion of a topological domain leads to restricted changes in its gene expression and affects interdomain communication.", "citation": "Galupa R, Picard C, Servant N et al. Inversion of a topological domain leads to restricted changes in its gene expression and affects interdomain communication. Development (Cambridge, England). 2022.", "doi": "10.1242/dev.200568", "pmcid": "PMC9148567", "url": "https://pubmed.ncbi.nlm.nih.gov/35502750/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35502750/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35502750", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse stem cells and embryos", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Large TAD inversion changes contacts with limited local expression effects, yet alters neighboring Xist.", "what_it_does_not_show": "Strong negative and positive locus contrast; changes in regulatory sequence position prevent topology-only inference.", "confounders_present": [ "Strong negative and positive locus contrast; changes in regulatory sequence position prevent topology-only inference." ], "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": [] }, "shared_components": [] }, { "n": 38, "pmid": "31522987", "title": "Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF.", "citation": "Hansen AS, Hsieh TS, Cattoglio C et al. Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF. Molecular cell. 2019.", "doi": "10.1016/j.molcel.2019.07.039", "pmcid": "PMC7251926", "url": "https://pubmed.ncbi.nlm.nih.gov/31522987/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31522987/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31522987", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CTCF RNA-binding-region loss disrupts roughly half the loops and selected expression with impaired clustering/binding.", "what_it_does_not_show": "Mutation changes RNA interactions and DNA occupancy, so direct biochemical causes remain.", "confounders_present": [ "Mutation changes RNA interactions and DNA occupancy, so direct biochemical causes 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": [] }, "shared_components": [] }, { "n": 39, "pmid": "31784727", "title": "Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations.", "citation": "Fulco CP, Nasser J, Jones TR et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nature genetics. 2019.", "doi": "10.1038/s41588-019-0538-0", "pmcid": "PMC6886585", "url": "https://pubmed.ncbi.nlm.nih.gov/31784727/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31784727/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31784727", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human cell CRISPRi screens", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Thousands of enhancer perturbations support activity-by-contact prediction of gene links.", "what_it_does_not_show": "Perturbed enhancer activity, not contact alone; prediction accuracy is not a necessity test of topology.", "confounders_present": [ "Perturbed enhancer activity, not contact alone; prediction accuracy is not a necessity test of topology." ], "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": [] }, "shared_components": [] }, { "n": 40, "pmid": "42457959", "title": "An encyclopedia of human enhancer-gene regulatory interactions.", "citation": "Gschwind AR, Mualim KS, Karbalayghareh A et al. An encyclopedia of human enhancer-gene regulatory interactions. Nature. 2026.", "doi": "10.1038/s41586-026-10781-4", "pmcid": "PMC13471189", "url": "https://pubmed.ncbi.nlm.nih.gov/42457959/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42457959/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID38014075" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "ENCODE-rE2G-final", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human enhancer perturbation and genetic datasets", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Final 2026 publication integrates over 92 million predicted links across 1,458 biosamples, with 10,356 perturbed pairs; promoter class and synergy contribute beyond contact.", "what_it_does_not_show": "Predicted links are not all experimentally tested. Updates preprint 38014075, counted once; enhancer interventions do not isolate topology.", "confounders_present": [ "Predicted links are not all experimentally tested. Updates preprint 38014075, counted once; enhancer interventions do not isolate topology." ], "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": [] }, "shared_components": [ "Updates preprint 38014075, excluded from count; earlier ENCODE/CRISPR datasets overlap prior predictive work." ] }, { "n": 41, "pmid": "19815776", "title": "Comprehensive mapping of long-range interactions reveals folding principles of the human genome.", "citation": "Lieberman-Aiden E, van Berkum NL, Williams L et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1181369", "pmcid": "PMC2858594", "url": "https://pubmed.ncbi.nlm.nih.gov/19815776/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19815776/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19815776", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Hi-C establishes genome-wide compartment and chromosome-territory contact patterns.", "what_it_does_not_show": "Population proximity ligation and polymer modelling do not prove individual permanent loops or transcriptional causality.", "confounders_present": [ "Population proximity ligation and polymer modelling do not prove individual permanent loops or transcriptional 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": [] }, "shared_components": [] }, { "n": 42, "pmid": "25497547", "title": "A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping.", "citation": "Rao SS, Huntley MH, Durand NC et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014.", "doi": "10.1016/j.cell.2014.11.021", "pmcid": "PMC5635824", "url": "https://pubmed.ncbi.nlm.nih.gov/25497547/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25497547/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25497547", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human and mammalian cell types", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Deep in-situ Hi-C maps domains, compartments and roughly ten thousand loops with convergent CTCF enrichment.", "what_it_does_not_show": "Association with activation; linked ErratumIn lacks PMID in metadata and body has not been audited.", "confounders_present": [ "Association with activation; linked ErratumIn lacks PMID in metadata and body has not been audited." ], "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": [] }, "shared_components": [] }, { "n": 43, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28985562", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph5, 1:RESULTS:paragraph24, 1:RESULTS:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human HCT116 cells", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Acute cohesin loss removes loop domains while compartments remain; restoration rapidly rebuilds loops, and only a minority of active genes changes.", "what_it_does_not_show": "Short-term gene output and protein pleiotropy; physical-loop necessity does not establish broad transcriptional necessity.", "confounders_present": [ "Short-term gene output and protein pleiotropy; physical-loop necessity does not establish broad transcriptional 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": [] }, "shared_components": [] }, { "n": 44, "pmid": "22495300", "title": "Topological domains in mammalian genomes identified by analysis of chromatin interactions.", "citation": "Dixon JR, Selvaraj S, Yue F et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012.", "doi": "10.1038/nature11082", "pmcid": "PMC3356448", "url": "https://pubmed.ncbi.nlm.nih.gov/22495300/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22495300/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22495300", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human and mouse stem and differentiated cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Hi-C identifies conserved topological domains and enriched boundary factors.", "what_it_does_not_show": "Bulk structural association lacks isolated functional perturbation.", "confounders_present": [ "Bulk structural association lacks isolated functional perturbation." ], "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": [] }, "shared_components": [] }, { "n": 45, "pmid": "28703188", "title": "Allelic reprogramming of 3D chromatin architecture during early mammalian development.", "citation": "Du Z, Zheng H, Huang B et al. Allelic reprogramming of 3D chromatin architecture during early mammalian development. Nature. 2017.", "doi": "10.1038/nature23263", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28703188/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28703188/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28703188", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse preimplantation embryos", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Low-input Hi-C shows slow postfertilization domain/compartment maturation and compaction partly without zygotic transcription.", "what_it_does_not_show": "Developmental staging and transcription inhibition do not independently manipulate every architecture mode.", "confounders_present": [ "Developmental staging and transcription inhibition do not independently manipulate every architecture mode." ], "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": [] }, "shared_components": [] }, { "n": 46, "pmid": "24335803", "title": "Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells.", "citation": "Zuin J, Dixon JR, van der Reijden MI et al. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proceedings of the National Academy of Sciences of the United States of America. 2014.", "doi": "10.1073/pnas.1317788111", "pmcid": "PMC3903193", "url": "https://pubmed.ncbi.nlm.nih.gov/24335803/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24335803/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24335803", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CTCF and cohesin depletion have distinct effects on domain contacts and gene groups.", "what_it_does_not_show": "Earlier partial depletion and mixed direct functions differ from acute complete architectural loss.", "confounders_present": [ "Earlier partial depletion and mixed direct functions differ from acute complete architectural 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": [] }, "shared_components": [] }, { "n": 47, "pmid": "31402173", "title": "A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers.", "citation": "El Khattabi L, Zhao H, Kalchschmidt J et al. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers. Cell. 2019.", "doi": "10.1016/j.cell.2019.07.011", "pmcid": "PMC7533040", "url": "https://pubmed.ncbi.nlm.nih.gov/31402173/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31402173/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31402173", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian lymphoid and stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Mediator core is required for Pol II recruitment but Mediator/Pol II are dispensable for regulatory DNA tethering.", "what_it_does_not_show": "Direct protein-function separation supports functional compatibility rather than contact sufficiency.", "confounders_present": [ "Direct protein-function separation supports functional compatibility rather than contact sufficiency." ], "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": [] }, "shared_components": [] }, { "n": 48, "pmid": "32822575", "title": "Genome-Scale Imaging of the 3D Organization and Transcriptional Activity of Chromatin.", "citation": "Su JH, Zheng P, Kinrot SS et al. Genome-Scale Imaging of the 3D Organization and Transcriptional Activity of Chromatin. Cell. 2020.", "doi": "10.1016/j.cell.2020.07.032", "pmcid": "PMC7851072", "url": "https://pubmed.ncbi.nlm.nih.gov/32822575/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32822575/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32822575", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "single mammalian cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Genome-scale imaging pairs more than a thousand loci and nascent transcripts with nuclear landmarks.", "what_it_does_not_show": "Simultaneous native-context observation is not intervention-driven causality.", "confounders_present": [ "Simultaneous native-context observation is not intervention-driven 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": [] }, "shared_components": [] }, { "n": 49, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37157000", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic stem cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Deep capture Micro-C detects nested microcompartments; many persist after extrusion loss or transcription inhibition.", "what_it_does_not_show": "Contact compartmentalization is an alternative mode; partial drug effects and selected captured regions limit broad proof.", "confounders_present": [ "Contact compartmentalization is an alternative mode; partial drug effects and selected captured regions limit broad 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": [] }, "shared_components": [] }, { "n": 50, "pmid": "30778195", "title": "Multiplex chromatin interactions with single-molecule precision.", "citation": "Zheng M, Tian SZ, Capurso D et al. Multiplex chromatin interactions with single-molecule precision. Nature. 2019.", "doi": "10.1038/s41586-019-0949-1", "pmcid": "PMC7001875", "url": "https://pubmed.ncbi.nlm.nih.gov/30778195/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30778195/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30778195", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "Drosophila cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ChIA-Drop resolves heterogeneous multivalent contacts at single-molecule precision.", "what_it_does_not_show": "Outside mammalian scope; native multiway contact does not specify transcriptional causal direction.", "confounders_present": [ "Outside mammalian scope; native multiway contact does not specify transcriptional 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": [] }, "shared_components": [] }, { "n": 51, "pmid": "35617427", "title": "Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation.", "citation": "Kraft K, Yost KE, Murphy SE et al. Polycomb-mediated genome architecture enables long-range spreading of H3K27 methylation. Proceedings of the National Academy of Sciences of the United States of America. 2022.", "doi": "10.1073/pnas.2201883119", "pmcid": "PMC9295753", "url": "https://pubmed.ncbi.nlm.nih.gov/35617427/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35617427/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35617427", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse stem cells/embryos and human induced stem cells", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Polycomb anchor deletions alter remote H3K27me3 and embryonic partner-gene repression.", "what_it_does_not_show": "Anchor DNA and PRC2 biochemical changes accompany contact loss; long-range topology-only necessity is unresolved.", "confounders_present": [ "Anchor DNA and PRC2 biochemical changes accompany contact loss; long-range topology-only necessity is 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": [] }, "shared_components": [] }, { "n": 52, "pmid": "31231024", "title": "Rapid Irreversible Transcriptional Reprogramming in Human Stem Cells Accompanied by Discordance between Replication Timing and Chromatin Compartment.", "citation": "Dileep V, Wilson KA, Marchal C et al. Rapid Irreversible Transcriptional Reprogramming in Human Stem Cells Accompanied by Discordance between Replication Timing and Chromatin Compartment. Stem cell reports. 2019.", "doi": "10.1016/j.stemcr.2019.05.021", "pmcid": "PMC6627004", "url": "https://pubmed.ncbi.nlm.nih.gov/31231024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31231024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31231024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human stem-cell endoderm differentiation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Transcription reprograms within a cell cycle while replication timing and compartments remain temporarily discordant.", "what_it_does_not_show": "Temporal discordance constrains synchronous primacy but does not prove causal independence.", "confounders_present": [ "Temporal discordance constrains synchronous primacy but does not prove causal independence." ], "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": [] }, "shared_components": [] }, { "n": 53, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38206813", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mammalian cultured cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "ZNF143 loss changes enhancer/promoter loops and CTCF/cohesin geometry.", "what_it_does_not_show": "Transcription-factor DNA recognition and promoter activities confound topology-only attribution.", "confounders_present": [ "Transcription-factor DNA recognition and promoter activities confound topology-only 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": [] }, "shared_components": [] }, { "n": 54, "pmid": "25959774", "title": "Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.", "citation": "Lupiáñez DG, Kraft K, Heinrich V et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015.", "doi": "10.1016/j.cell.2015.04.004", "pmcid": "PMC4791538", "url": "https://pubmed.ncbi.nlm.nih.gov/25959774/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25959774/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25959774", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph15. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human limb-malformation families and matched mouse edits", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted.", "what_it_does_not_show": "Boundary-preserving shorter deletions retain normal limbs/expression, narrowing distance-only explanation; regulatory-content changes and selected developmental landscape still limit generalization.", "confounders_present": [ "Boundary-preserving shorter deletions retain normal limbs/expression, narrowing distance-only explanation; regulatory-content changes and selected developmental landscape still limit generalization." ], "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": [] }, "shared_components": [] }, { "n": 55, "pmid": "31127282", "title": "Acute depletion of CTCF directly affects MYC regulation through loss of enhancer-promoter looping.", "citation": "Hyle J, Zhang Y, Wright S et al. Acute depletion of CTCF directly affects MYC regulation through loss of enhancer-promoter looping. Nucleic acids research. 2019.", "doi": "10.1093/nar/gkz462", "pmcid": "PMC6648894", "url": "https://pubmed.ncbi.nlm.nih.gov/31127282/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31127282/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31127282", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human B-ALL and erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Acute CTCF loss lowers MYC and distant contact in SEM but has minimal global and little HUDEP2 MYC effect.", "what_it_does_not_show": "Lineage-specific necessity with direct protein functions; cannot generalize from a responsive tumour line.", "confounders_present": [ "Lineage-specific necessity with direct protein functions; cannot generalize from a responsive tumour line." ], "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": [] }, "shared_components": [] }, { "n": 56, "pmid": "31776509", "title": "Chromatin structure dynamics during the mitosis-to-G1 phase transition.", "citation": "Zhang H, Emerson DJ, Gilgenast TG et al. Chromatin structure dynamics during the mitosis-to-G1 phase transition. Nature. 2019.", "doi": "10.1038/s41586-019-1778-y", "pmcid": "PMC6895436", "url": "https://pubmed.ncbi.nlm.nih.gov/31776509/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31776509/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31776509", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "synchronized mouse erythroid cells", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Postmitotic contacts reform with distinct kinetics; regulatory interactions can precede CTCF/cohesin loops.", "what_it_does_not_show": "Time-course order and synchronization alone do not isolate causal architecture.", "confounders_present": [ "Time-course order and synchronization alone do not isolate causal architecture." ], "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": [] }, "shared_components": [] }, { "n": 57, "pmid": "22495304", "title": "Spatial partitioning of the regulatory landscape of the X-inactivation centre.", "citation": "Nora EP, Lajoie BR, Schulz EG et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature. 2012.", "doi": "10.1038/nature11049", "pmcid": "PMC3555144", "url": "https://pubmed.ncbi.nlm.nih.gov/22495304/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22495304/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22495304", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse X-inactivation centre", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "5C and microscopy identify domains; boundary disruption causes ectopic contacts and transcriptional misregulation.", "what_it_does_not_show": "Local regulatory content and X-inactivation specialization limit global inference.", "confounders_present": [ "Local regulatory content and X-inactivation specialization limit global inference." ], "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": [] }, "shared_components": [] }, { "n": 58, "pmid": "29094699", "title": "Two independent modes of chromatin organization revealed by cohesin removal.", "citation": "Schwarzer W, Abdennur N, Goloborodko A et al. Two independent modes of chromatin organization revealed by cohesin removal. Nature. 2017.", "doi": "10.1038/nature24281", "pmcid": "PMC5687303", "url": "https://pubmed.ncbi.nlm.nih.gov/29094699/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29094699/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29094699", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 8:Main text (unsectioned body paragraphs), 0:Disappearance of TADs and peaks, 2:Transcriptional changes upon TAD loss. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse adult liver", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Adult hepatocyte Nipbl deletion removes TADs and peaks while compartments strengthen; 1,124 genes and 1,107 exogenic regions change, yet TADs also disappear in expression-stable regions.", "what_it_does_not_show": "Chronic loader loss affects protein biology; liver context and residual fine structures must be retained.", "confounders_present": [ "Chronic loader loss affects protein biology; liver context and residual fine structures must be retained." ], "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": [] }, "shared_components": [] }, { "n": 59, "pmid": "34292939", "title": "Induction of a chromatin boundary in vivo upon insertion of a TAD border.", "citation": "Willemin A, Lopez-Delisle L, Bolt CC et al. Induction of a chromatin boundary in vivo upon insertion of a TAD border. PLoS genetics. 2021.", "doi": "10.1371/journal.pgen.1009691", "pmcid": "PMC8330945", "url": "https://pubmed.ncbi.nlm.nih.gov/34292939/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34292939/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34292939", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "mouse embryonic development", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Relocated HoxD boundary recruits architectural proteins and divides a host domain in vivo.", "what_it_does_not_show": "Structural sufficiency is demonstrated; abstract does not establish corresponding transcriptional primacy.", "confounders_present": [ "Structural sufficiency is demonstrated; abstract does not establish corresponding transcriptional primacy." ], "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": [] }, "shared_components": [] }, { "n": 60, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31124784", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "live mouse embryonic stem cells", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Sox2 requires SCR enhancer yet contemporaneous bursts do not correlate with enhanced spatial proximity.", "what_it_does_not_show": "SCR deletion validates enhancer dependence and lag-aligned analysis is null within examined window; labels lie 5–8 kb from elements and finite spatial/time resolution cannot exclude brief or historical contacts.", "confounders_present": [ "SCR deletion validates enhancer dependence and lag-aligned analysis is null within examined window; labels lie 5–8 kb from elements and finite spatial/time resolution cannot exclude brief or historical 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": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 64, "verified": 64, "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": "Independent contact maps, fixed-cell tracing and live-cell controls reproducibly reveal dynamic loops, domains and compartments. Β reflects the noncausal existence formulation; physical formation mechanisms have direct perturbational support but do not transfer to transcriptional primacy.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Mechanistic plausibility plus in vitro reconstitution or simplified cellular support caps at Γ.", "specific_trigger": "Short-term nascent transcription and many fine enhancer-promoter contacts persist after loop-extrusion factor loss; large endogenous edits are often buffered. Positive local and activation-context effects do not establish broad rate-limiting primacy. Protein chemistry, activation/maintenance timing and compartment modes prevent a global topology-only inference.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Three-dimensional genome folding is a primary causal determinant of transcriptional regulation across mammalian loci.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Loop/contact enrichment and reporter-only behavior cap inference to broad endogenous regulation, while endogenous boundary/allele comparisons with functional outputs cross scoped causal thresholds. The assembled SC2 set is evaluated jointly; individual limitations do not re-cap a set that narrows distinct errors. For SC3, no positive topology-specific global primacy experiment qualifies, so local threshold crossings do not lift its Γ ceiling.", "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": [ "Observation of features is not a claim of transcriptional causality." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Independent contact maps, fixed-cell tracing and live-cell controls reproducibly reveal dynamic loops, domains and compartments. Β reflects the noncausal existence formulation; physical formation mechanisms have direct perturbational support but do not transfer to transcriptional primacy.", "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": "yes", "qualifying_evidence_citation": "PMID34585664, PMID22682246, PMID38452764, PMID30742094, PMID26276636, PMID25959774", "gamma_hard_rules_triggered": [ "Native functional comparisons, rather than contact enrichment alone, carry the scoped grade." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Human structural variants recreated in mice, boundary-preserving controls, CTCF motif inversions and enhancer-dependent directed globin activation converge on causal contribution at defined endogenous loci. They fail differently; separation-of-function LDB1 controls show that contacts also require competent biochemistry. Ζ applies to specific architectural contributions, not universal necessity or contact sufficiency.", "ceiling_from_boundary_check": "Δ or higher" }, { "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": [ "Broad topology-specific necessity and rate-limiting sufficiency remain absent." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Short-term nascent transcription and many fine enhancer-promoter contacts persist after loop-extrusion factor loss; large endogenous edits are often buffered. Positive local and activation-context effects do not establish broad rate-limiting primacy. Protein chemistry, activation/maintenance timing and compartment modes prevent a global topology-only inference.", "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": "For a separate formation-mechanism claim, target each architectural mode with reversible endogenous perturbation and orthogonal structural measurement; existence is already well corroborated." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.", "satisfied": "yes", "supporting_evidence": [ "[7] Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates.", "[23] LDB1 tethering reactivates native beta-globin, requiring the distant LCR.", "[26] Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction.", "[34] Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype.", "[36] CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity.", "[54] Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.", "satisfied": "yes", "supporting_evidence": [ "[7] Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates.", "[23] LDB1 tethering reactivates native beta-globin, requiring the distant LCR.", "[26] Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction.", "[34] Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype.", "[36] CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity.", "[54] Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Independent causal tests across loci or systems\n- Specificity beyond global transcriptional collapse\n- Narrowing of key alternatives", "satisfied": "yes", "supporting_evidence": [ "[7] Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates.", "[23] LDB1 tethering reactivates native beta-globin, requiring the distant LCR.", "[26] Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction.", "[34] Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype.", "[36] CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity.", "[54] Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Robust endogenous causality\n- Reproducibility across loci/cell states within scope\n- Strong evidence that the proposed mechanism is not a downstream correlate", "satisfied": "no", "supporting_evidence": [ "[7] Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates.", "[23] LDB1 tethering reactivates native beta-globin, requiring the distant LCR.", "[26] Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction.", "[34] Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype.", "[36] CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity.", "[54] Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted." ], "what_would_cross_it": "Topology-specific endogenous loss/restoration with preserved factor binding, broader prespecified loci and lineages, and time-resolved functional output would extend reproducibility beyond scoped causal contribution." }, { "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": "Matched endogenous topology-only and biochemical-only perturbations in a preregistered representative locus panel during activation and maintenance, with viability, replication and nascent RNA controls plus independent rescue." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Boundary-preserving DelBS/DbfS alleles retain normal limbs and expression (25959774).", "LCR-deleted alleles and homozygous deletion resolve ZF-SA response and primer cross-reactivity (22682246).", "Looping-intact LDB1 DD4/5 fails promoter recruitment/activation (24874989).", "Sox2 SCR deletion, MS2-negative cells, transcription inhibitor and shuffled lag controls (31124784).", "Nora auxin controls, nondividing cells, dose and low-expression rescue distinguish acute from late viability effects (28525758).", "Rao inactive genes mostly remain inactive; Hsieh nascent RNA limits mature-transcript buffering (28985562,36471071).", "Shh promoter/proximal activation and unchanged Lmbr1 distinguish distal need; six-hour assay avoids 24-hour cell death (36097291)." ], "note": "Lineages, activation stage, genomic distance, locus and architectural mode are specified before the response. Fly studies are comparative, not extra mammalian replication. Positive and null native edits show genuine scope heterogeneity. Bounded absence of a broad topology-only experiment is not an exhaustive no-study claim." }, "falsification_patterns_met": [ { "pattern": "Loss of architectural features preserves much transcription", "evidence": "Hsieh three-hour nascent RNA, Rao 87% relatively stable active genes and Shh endogenous boundary edits (36471071,28985562,31511252).", "downgrade_applied": false }, { "pattern": "Restoring contact alone fails activation", "evidence": "LDB1 DD4/5 mutant restores globin looping without promoter Pol II or transcription (24874989).", "downgrade_applied": false }, { "pattern": "Proximity does not track contemporaneous enhancer-dependent bursts", "evidence": "Sox2 SCR deletion control versus null distance/burst and lag analysis; Shh activation can increase distance (31124784,31494034).", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Population contact enrichment treated as permanent single-cell loops", "where": "Bintu, Fbn2 and Hsieh terminology checks separate probabilities, distances and dynamic domains." }, { "pitfall": "Protein necessity treated as topology-specific necessity", "where": "CTCF promoter function and cohesin TF target search are explicit alternatives." }, { "pitfall": "Reporter nonlinearity generalized to native genome primacy", "where": "Zuin neutral-TAD transgene and founder-map probabilities remain bounded." }, { "pitfall": "Global transcriptional persistence treated as no regulatory function", "where": "Schwarzer gene/exogenic changes, Nora late changes and local human/mouse phenotypes retained." }, { "pitfall": "Negative maintenance test generalized to all activation", "where": "Distant Shh activation and neuron gene-class dependence are separately scored." }, { "pitfall": "Preprints or repeated globin assays counted as independent lines", "where": "ENCODE final replaces preprint; LDB1 reports share a platform; study groups logged." } ], "causal_tally_audit": { "tally_claimed_by_document": 12, "tally_after_audit": 12, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Twelve especially discriminating positive/negative contrasts are flagged; this is not twelve independent positive proofs.", "SC2 positive threshold set is restricted to native locus/boundary or enhancer-dependent functional comparisons. Structural imaging, local expression associations and global nulls are not positive SC3 thresholds." ] }, "steelman": { "case_one_rung_higher": "One rung above Γ is Δ: endogenous human/mouse boundary phenotypes, orientation edits and forced native-locus activation could be generalized to a substantial architectural contribution across loci.", "case_one_rung_lower": "One rung below Γ is Β: genome-wide contact-expression patterns and persistent transcripts could leave broad primacy as correlation, with positive protein perturbations explained entirely by biochemical effects.", "which_rejected": "Δ is rejected for broad primary SC3 because the context and topology-specificity of the positive causal tests do not match that scope. Β understates the mechanistic content supplied by native locus manipulations, controlled enhancer dependence and distance-dependent activation. Local SC2 independently receives Ζ, without substituting that success for broad primacy.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Preregister representative endogenous loci across two mammalian lineages, proximal/distal enhancers and activation/maintenance. Cross acute topology-specific edits or separation alleles with biochemical-only defects, and independently restore architecture without restoring original cofactor surfaces." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 11 selected partial-body examinations; evidence density, independent replication and heterogeneity of controls set the confidence; access depth and belief in correctness do not.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched gate is SC3, yielding Γ. SC2 reaches Ζ through independent endogenous boundary edits, allele-resolved human/mouse developmental tests and locus-directed functional rescue, interpreted as architectural contribution rather than a sole switch. SC1 is an existence statement: Β records robust structural observation without pretending existence itself proves regulatory causality. Its empirical reality is well established and is not refuted by this causal ladder." }, "role_of_mechanism": { "classification": "permissive factor", "derivation_step_matched": 4, "derivation": "Step 1 does not classify all architecture as produced by transcription: local boundary function can precede output. Step 2 is exceeded by functional local perturbations. Step 3 fails broad necessity/sufficiency and rate-limiting primacy. Step 4 matches restricted necessity for enhancer access/insulation with competent biochemistry; this permissive classification is made before model ranking and applies to the bounded regulatory contribution.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "The named artifact is published mechanistic output: 2024 endogenous boundary dissection, 2025 LDB1 acute connectivity tests refining controls, and the 2026 ENCODE predictive benchmark broadening scope. None of it is a topology-only primacy test, which is what SC3's boundary check requires, and consistent with the Stability entry no such matched topology/biochemistry rescue panel was identified as underway. No live trial or promised outcome claimed.", "justification": "The named artifact is published mechanistic output: 2024 endogenous boundary dissection, 2025 LDB1 acute connectivity tests refining controls, and the 2026 ENCODE predictive benchmark broadening scope. None of it is a topology-only primacy test, which is what SC3's boundary check requires, and consistent with the Stability entry no such matched topology/biochemistry rescue panel was identified as underway. No live trial or promised outcome claimed." }, "stability": { "value": "Stable", "trigger": "No verified imminent result is identified that would specifically cross broad topology primacy. A matched topology/biochemical rescue panel could change the level.", "justification": "No verified imminent result is identified that would specifically cross broad topology primacy. A matched topology/biochemical rescue panel could change the level." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No single field-implied level is defensible from conflicting framings: reviews and grant framing commonly present folding as a primary determinant of mammalian transcription, while the acute-depletion literature (36471071, 28985562, 29094699) is presented by its own authors as showing most expression maintained. No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Preregister representative endogenous loci across two mammalian lineages, proximal/distal enhancers and activation/maintenance. Cross acute topology-specific edits or separation alleles with biochemical-only defects, and independently restore architecture without restoring original cofactor surfaces.", "readout": "Nascent transcription/burst kinetics, enhancer activity, direct factor occupancy, live distances/contact probabilities, cell cycle and viability during perturbation and recovery", "critical_control": "Expression/binding-matched alleles, untagged drug control, promoter competence, replication-stress control, unchanged enhancer sequence, and timed activation history", "supporting_result": "Topology-specific loss systematically changes preregistered output and orthogonal topology rescue restores it despite matched chemistry, establishing necessity and rate limitation within stated scope", "falsifying_result": "Output persists or is rescued by biochemical competence without restored topology; effects occur only after general collapse or selected responder loci" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Topology-only perturbation and orthogonal rescue preserving factor biochemistry.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Representative prespecified loci and lineages rather than outcome-selected responsive loci.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Matched activation-versus-maintenance histories and longer recovery with nascent output.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Same-cell topology, factor binding and transcription at sufficient temporal/spatial resolution.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Discrimination of stable boundary loops, transient encounters and microcompartments.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Human allele-resolved functional effects beyond selected developmental and globin loci.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Quantitative reconciliation of contact probability, 3D distance and nonlinear promoter memory.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Original supplements and unresolved Rao 2014 correction-body audit; access boundaries retained.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "60 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; primary leads were resolved to canonical originals before counting. See scispace-discovery.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "The index entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "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 local edits, allele-resolved developmental variants and dose/recovery controls were considered. Their convergent set raises SC2 to Ζ; broad primacy SC3 still lacks representative topology-only necessity/sufficiency separated from protein function and reverse causality. No demand for an impossible clinical RCT is imposed." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Endogenous local edits, allele-resolved developmental variants and dose/recovery controls were considered. Their convergent set raises SC2 to Ζ; broad primacy SC3 still lacks representative topology-only necessity/sufficiency separated from protein function and reverse causality. No demand for an impossible clinical RCT is imposed." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Endogenous local edits, allele-resolved developmental variants and dose/recovery controls were considered. Their convergent set raises SC2 to Ζ; broad primacy SC3 still lacks representative topology-only necessity/sufficiency separated from protein function and reverse causality. No demand for an impossible clinical RCT is imposed." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Endogenous local edits, allele-resolved developmental variants and dose/recovery controls were considered. Their convergent set raises SC2 to Ζ; broad primacy SC3 still lacks representative topology-only necessity/sufficiency separated from protein function and reverse causality. No demand for an impossible clinical RCT is imposed." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Endogenous local edits, allele-resolved developmental variants and dose/recovery controls were considered. Their convergent set raises SC2 to Ζ; broad primacy SC3 still lacks representative topology-only necessity/sufficiency separated from protein function and reverse causality. No demand for an impossible clinical RCT is imposed." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 64, "claims_verified": 64, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Acute LDB1 loss and engineered recruitment alter multi-enhancer networks; many connections persist without CTCF/cohesin/YY1. LDB1 transcriptional biochemistry and contact changes are intertwined; one lineage does not establish genome-wide primacy. Updates preprint 39229045.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "Cohesin is required for synthetic activation from distant Shh enhancers, while promoter and proximal activation remain independent. Artificial activation and acute protein loss do not isolate topology from all protein functions; distance and context constrain necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "Most enhancer-promoter interactions and nascent transcription remain after three-hour CTCF/cohesin/WAPL/YY1 depletion. Short-term maintenance is tested; activation and later effects remain open. Cohesin affects transcription-factor binding.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph20, 1:Results:paragraph25, 1:Results:paragraph31, 1:Results:paragraph47, 3:Methods:paragraph0, 3:Methods:paragraph39. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "Imaging shows stochastic domain intermingling; cohesin loss reduces contacts, whereas CTCF/WAPL loss increases cohesin-dependent mixing and alters boundary-proximal bursting. Population TAD loss does not imply increased single-cell ectopic contact; protein depletion has biochemical effects.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Dose-dependent CTCF depletion and restoration change domain insulation; compartments persist and nondividing cells need CTCF for insulation. Physical insulation recovers but most expression changes do not fully reset after washout; early downregulated promoters show direct CTCF binding. Late viability and direct protein functions constrain topology attribution.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "Tandem CTCF sites and sequence context provide insulation and weaken local contacts. Reporter insulation and DNA/protein binding effects cannot establish endogenous transcriptional primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Deleting the beta-globin 3-prime HS1 boundary activates fetal haemoglobin through an ectopic distal enhancer; inversion insulates. Endogenous locus evidence; motif orientation and protein recruitment are linked. No patient clinical outcome or broad primacy test.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "Lineage-specific CTCF binding and motif deletion at RBM38 alter enhancer interaction and erythropoiesis. One endogenous locus and regulatory DNA edit; topology-only attribution and exact scope need controls.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "Acute CTCF loss alters accessibility near binding sites and selected gene output without a large global transcriptional change. Accessibility, CTCF partners and contact changes cannot by themselves separate direct biochemical regulation from topology.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "Immediate-early activation and short Fos contacts persist without cohesin; longer-loop secondary response and synapse genes show greater dependence. Dependence is gene-class and distance specific; chronic developmental and direct protein effects remain alternative causes.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Eight-timepoint maps associate enhancer acetylation, expression and loop changes with reciprocal timing. Temporal associations do not isolate causality; transcription itself can impede loops.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "Nearly a thousand developmental enhancers show moderate tissue-specific increases in contacts; stable contacts can persist without enhancer. Activity-contact correlation and enhancer absence do not demonstrate broad topology necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Dense enhancer repositioning reveals nonlinear relationships between contact probability, enhancer strength and promoter output. Engineered eGFP/Sox2-SCR transgene in a neutral TAD with internal CTCF sites removed; founder contact maps infer probabilities. Nonlinear model fit is not direct observation of momentary endogenous contact-to-burst causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Enhancer action depends on genomic distance:paragraph0, 1:Enhancer action depends on genomic distance:paragraph2, 1:Enhancer action depends on genomic distance:paragraph3, 1:Enhancer action depends on genomic distance:paragraph4, 2:Enhancer contacts modulate burst frequency:paragraph0, 2:Enhancer contacts modulate burst frequency:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "Promoter CTCF binding loss decreases selected distant contacts and expression; tethered CTCF restores both. CTCF tethering restores biochemical activities too; adult-tissue breadth is correlational.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Enhancer-promoter topology is permissive at specification and better correlates with activity during terminal differentiation. Outside registered mammalian scope; contact/activity observations do not prove necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "BET inhibition and BRD4 loss reduce transcription while enhancer-promoter contacts persist. Protein and solvent interventions are not phase-state specific; contact persistence need not exclude transient interactions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "Shh activation accompanies decreased spatial enhancer proximity; synthetic activation reproduces it with PARP dependence. One locus; fixed-cell distance and ligation contact differ; contact events below resolution may remain.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "Live imaging resolves regulatory-factor clustering and frequent enhancer-gene proximity within nanoenvironments. Physical proximity and recruitment do not isolate topology as the initiating causal variable.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C19", "text": "NIPBL or WAPL depletion each misregulates roughly two thousand genes; co-depletion restores most misexpression. Compensatory protein perturbation supports cohesin balance but cannot exclude non-topological biochemical functions.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C20", "text": "TATA deletion preserves looping despite transcription loss; activation-deficient LDB1 restores contact without Mediator/cohesin. Looping sufficiency is explicitly limited; linked biochemical functions require separation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C21", "text": "LDB1 DD4/5 mutant preserves dimerization and looping but lacks transcriptional activation and coregulator recruitment. Matched separation at one locus constrains a loop-only explanation; mutation has identified biochemical consequences.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph9, 0:Results:paragraph12, 0:Results:paragraph14, 0:Results:paragraph24. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "Forced globin contact increases burst fraction, with little burst-size effect. Related LDB1 platform and locus; forced protein recruitment is not topology-only manipulation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "LDB1 tethering reactivates native beta-globin, requiring the distant LCR. Artificial tethering in a deficient background can restore cofactor functions; locus requirement cannot establish universal primacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "Forced LDB1 recruitment reactivates developmentally silenced globins and changes LCR contacts. Same tethering family; high output in culture is not clinical efficacy or general topology sufficiency.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "ZF-LDB1 raises fetal haemoglobin and reduces hypoxic sickling compared with selected drug regimens. Ex vivo gene delivery; related globin programme; in vivo safety and broad transcriptional role untested.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "Four CTCF motif disruptions fuse domains and increase ANO1-enhancer contact with FGF3 and FGF3 induction. Regulatory DNA/protein changes accompany topology; tumour association differs from autonomous initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "Micro-C resolves fine enhancer/promoter structures; acute transcription inhibition disrupts fine features but not higher architecture. Intervention supports reverse causality as well as coupling; drugs are pleiotropic.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C28", "text": "Cohesin loss removes TADs while PRC1-dependent contacts persist or strengthen and repression changes. Distinct architectural modes and direct PRC1 biochemical repression prevent universal loop-extrusion attribution.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C29", "text": "Multiple Shh TAD/boundary edits leave expression and phenotype largely intact; one larger deletion affects neighboring Mnx1. Endogenous negative test; buffering, locus choice and larger-edit regulatory content limit generalization.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C30", "text": "Fbn2 boundary loops are rare and dynamic, with roughly 3–6.5 percent occupancy and 10–30-minute lifetimes. One locus and Bayesian state inference; population loops do not mean permanent structures in every cell.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Main text:paragraph3, 1:Main text:paragraph9, 1:Main text:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C31", "text": "Chromatin tracing detects heterogeneous TAD-like conformations; cohesin loss removes preferred boundary positions but not single-cell domains. Population-domain loss differs from absence of local conformations; fixed imaging is not transcriptional causal proof.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "Cohesin, CTCF, WAPL and PDS5 perturbations change domains, boundaries and loop lengths differently. Protein effects establish structural control, not necessarily broad transcriptional initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C33", "text": "Allele-specific balancer rearrangements disrupt many contacts while most expression remains stable. Outside mammalian scope; developmental compensation and complex rearrangements remain.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "Serial inversions create tissue-specific stripes, ectopic transcription and malformations; anchor deletion rescues phenotype. Endogenous functional test with rescue; selected enhancer-rich landscape and regulatory-sequence effects limit breadth.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "Allelic boundary edits at Prdm14 change extrusion trajectories; activation can cross a prominent boundary and need not require paused looping. Context-specific endogenous edits separate simplistic boundary loops; enhancer activity contributes to architecture.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "CTCF motif inversion reconfigures contacts and enhancer/promoter expression specificity. Local motif orientation preserves some sequence content but changes protein geometry; limited loci.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "Large TAD inversion changes contacts with limited local expression effects, yet alters neighboring Xist. Strong negative and positive locus contrast; changes in regulatory sequence position prevent topology-only inference.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "CTCF RNA-binding-region loss disrupts roughly half the loops and selected expression with impaired clustering/binding. Mutation changes RNA interactions and DNA occupancy, so direct biochemical causes remain.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "Thousands of enhancer perturbations support activity-by-contact prediction of gene links. Perturbed enhancer activity, not contact alone; prediction accuracy is not a necessity test of topology.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "Final 2026 publication integrates over 92 million predicted links across 1,458 biosamples, with 10,356 perturbed pairs; promoter class and synergy contribute beyond contact. Predicted links are not all experimentally tested. Updates preprint 38014075, counted once; enhancer interventions do not isolate topology.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "Hi-C establishes genome-wide compartment and chromosome-territory contact patterns. Population proximity ligation and polymer modelling do not prove individual permanent loops or transcriptional causality.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Deep in-situ Hi-C maps domains, compartments and roughly ten thousand loops with convergent CTCF enrichment. Association with activation; linked ErratumIn lacks PMID in metadata and body has not been audited.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "Acute cohesin loss removes loop domains while compartments remain; restoration rapidly rebuilds loops, and only a minority of active genes changes. Short-term gene output and protein pleiotropy; physical-loop necessity does not establish broad transcriptional necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph0, 1:RESULTS:paragraph5, 1:RESULTS:paragraph24, 1:RESULTS:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "Hi-C identifies conserved topological domains and enriched boundary factors. Bulk structural association lacks isolated functional perturbation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C45", "text": "Low-input Hi-C shows slow postfertilization domain/compartment maturation and compaction partly without zygotic transcription. Developmental staging and transcription inhibition do not independently manipulate every architecture mode.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "CTCF and cohesin depletion have distinct effects on domain contacts and gene groups. Earlier partial depletion and mixed direct functions differ from acute complete architectural loss.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "Mediator core is required for Pol II recruitment but Mediator/Pol II are dispensable for regulatory DNA tethering. Direct protein-function separation supports functional compatibility rather than contact sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Genome-scale imaging pairs more than a thousand loci and nascent transcripts with nuclear landmarks. Simultaneous native-context observation is not intervention-driven causality.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "Deep capture Micro-C detects nested microcompartments; many persist after extrusion loss or transcription inhibition. Contact compartmentalization is an alternative mode; partial drug effects and selected captured regions limit broad proof.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "ChIA-Drop resolves heterogeneous multivalent contacts at single-molecule precision. Outside mammalian scope; native multiway contact does not specify transcriptional causal direction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Polycomb anchor deletions alter remote H3K27me3 and embryonic partner-gene repression. Anchor DNA and PRC2 biochemical changes accompany contact loss; long-range topology-only necessity is unresolved.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "Transcription reprograms within a cell cycle while replication timing and compartments remain temporarily discordant. Temporal discordance constrains synchronous primacy but does not prove causal independence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "ZNF143 loss changes enhancer/promoter loops and CTCF/cohesin geometry. Transcription-factor DNA recognition and promoter activities confound topology-only attribution.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "Human structural variants and recreated mouse alleles rewire enhancer access and developmental expression when boundaries are disrupted. Boundary-preserving shorter deletions retain normal limbs/expression, narrowing distance-only explanation; regulatory-content changes and selected developmental landscape still limit generalization.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Acute CTCF loss lowers MYC and distant contact in SEM but has minimal global and little HUDEP2 MYC effect. Lineage-specific necessity with direct protein functions; cannot generalize from a responsive tumour line.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Postmitotic contacts reform with distinct kinetics; regulatory interactions can precede CTCF/cohesin loops. Time-course order and synchronization alone do not isolate causal architecture.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "5C and microscopy identify domains; boundary disruption causes ectopic contacts and transcriptional misregulation. Local regulatory content and X-inactivation specialization limit global inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "Adult hepatocyte Nipbl deletion removes TADs and peaks while compartments strengthen; 1,124 genes and 1,107 exogenic regions change, yet TADs also disappear in expression-stable regions. Chronic loader loss affects protein biology; liver context and residual fine structures must be retained.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 8:Main text (unsectioned body paragraphs), 0:Disappearance of TADs and peaks, 2:Transcriptional changes upon TAD loss. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Relocated HoxD boundary recruits architectural proteins and divides a host domain in vivo. Structural sufficiency is demonstrated; abstract does not establish corresponding transcriptional primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C60", "text": "Sox2 requires SCR enhancer yet contemporaneous bursts do not correlate with enhanced spatial proximity. SCR deletion validates enhancer dependence and lag-aligned analysis is null within examined window; labels lie 5–8 kb from elements and finite spatial/time resolution cannot exclude brief or historical contacts.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Independent contact maps, fixed-cell tracing and live-cell controls reproducibly reveal dynamic loops, domains and compartments. Β reflects the noncausal existence formulation; physical formation mechanisms have direct perturbational support but do not transfer to transcriptional primacy.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 3, 4, 5, 11, 12, 15, 17, 18, 27, 28, 30, 31, 32, 36, 38, 41, 42, 43, 44, 45, 46, 48, 49, 50, 52, 53, 56, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Human structural variants recreated in mice, boundary-preserving controls, CTCF motif inversions and enhancer-dependent directed globin activation converge on causal contribution at defined endogenous loci. They fail differently; separation-of-function LDB1 controls show that contacts also require competent biochemistry. Ζ applies to specific architectural contributions, not universal necessity or contact sufficiency.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 43, 46, 47, 48, 49, 51, 53, 54, 55, 57, 58, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Short-term nascent transcription and many fine enhancer-promoter contacts persist after loop-extrusion factor loss; large endogenous edits are often buffered. Positive local and activation-context effects do not establish broad rate-limiting primacy. Protein chemistry, activation/maintenance timing and compartment modes prevent a global topology-only inference.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 7, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 23, 26, 27, 28, 29, 30, 31, 33, 34, 35, 37, 39, 40, 43, 45, 46, 47, 49, 52, 54, 55, 56, 58, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "3D genome features are real and specific architectural changes regulate defined loci; broad topological primacy over mammalian transcription is not established.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 54, 36, 3, 21, 60, 58 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39721581", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3" ] }, { "n": 2, "citation": "Kane L, Williamson I, Flyamer IM et al. Cohesin is required for long-range enhancer action at the Shh locus. Nature structural & molecular biology. 2022.", "tier": "A", "kind": "primary", "pmid": "36097291", "doi": "10.1038/s41594-022-00821-8", "url": "https://pubmed.ncbi.nlm.nih.gov/36097291/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36097291", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC2", "CSC3" ] }, { "n": 3, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36471071", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph8, 1:Results:paragraph17, 1:Results:paragraph20, 1:Results:paragraph25, 1:Results:paragraph31, 1:Results:paragraph47, 3:Methods:paragraph0, 3:Methods:paragraph39. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 4, "citation": "Luppino JM, Park DS, Nguyen SC et al. Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes. Nature genetics. 2020.", "tier": "A", "kind": "primary", "pmid": "32572210", "doi": "10.1038/s41588-020-0647-9", "url": "https://pubmed.ncbi.nlm.nih.gov/32572210/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32572210", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC2", "CSC3" ] }, { "n": 5, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28525758", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph7, 1:Results:paragraph10, 1:Results:paragraph14, 1:Results:paragraph15, 1:Results:paragraph18. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2", "CSC3" ] }, { "n": 6, "citation": "Huang H, Zhu Q, Jussila A et al. CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains. Nature genetics. 2021.", "tier": "A", "kind": "primary", "pmid": "34002095", "doi": "10.1038/s41588-021-00863-6", "url": "https://pubmed.ncbi.nlm.nih.gov/34002095/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34002095", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2" ] }, { "n": 7, "citation": "Himadewi P, Wang XQD, Feng F et al. 3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression. eLife. 2021.", "tier": "A", "kind": "primary", "pmid": "34585664", "doi": "10.7554/eLife.70557", "url": "https://pubmed.ncbi.nlm.nih.gov/34585664/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34585664", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2", "CSC3" ] }, { "n": 8, "citation": "Qi Q, Cheng L, Tang X et al. Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis. Blood. 2021.", "tier": "A", "kind": "primary", "pmid": "33512425", "doi": "10.1182/blood.2020005780", "url": "https://pubmed.ncbi.nlm.nih.gov/33512425/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33512425", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC2" ] }, { "n": 9, "citation": "Xu B, Wang H, Wright S et al. Acute depletion of CTCF rewires genome-wide chromatin accessibility. Genome biology. 2021.", "tier": "A", "kind": "primary", "pmid": "34429148", "doi": "10.1186/s13059-021-02466-0", "url": "https://pubmed.ncbi.nlm.nih.gov/34429148/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34429148", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC2", "CSC3" ] }, { "n": 10, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID35471149", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC2", "CSC3" ] }, { "n": 11, "citation": "Reed KSM, Davis ES, Bond ML et al. Temporal analysis suggests a reciprocal relationship between 3D chromatin structure and transcription. 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Cell. 2014.", "tier": "A", "kind": "primary", "pmid": "25497547", "doi": "10.1016/j.cell.2014.11.021", "url": "https://pubmed.ncbi.nlm.nih.gov/25497547/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25497547", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C42", "CSC1" ] }, { "n": 43, "citation": "Rao SSP, Huang SC, Glenn St Hilaire B et al. Cohesin Loss Eliminates All Loop Domains. 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Proceedings of the National Academy of Sciences of the United States of America. 2014.", "tier": "A", "kind": "primary", "pmid": "24335803", "doi": "10.1073/pnas.1317788111", "url": "https://pubmed.ncbi.nlm.nih.gov/24335803/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24335803", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C46", "CSC1", "CSC2", "CSC3" ] }, { "n": 47, "citation": "El Khattabi L, Zhao H, Kalchschmidt J et al. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers. Cell. 2019.", "tier": "A", "kind": "primary", "pmid": "31402173", "doi": "10.1016/j.cell.2019.07.011", "url": "https://pubmed.ncbi.nlm.nih.gov/31402173/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31402173", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C47", "CSC2", "CSC3" ] }, { "n": 48, "citation": "Su JH, Zheng P, Kinrot SS et al. Genome-Scale Imaging of the 3D Organization and Transcriptional Activity of Chromatin. 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Stem cell reports. 2019.", "tier": "A", "kind": "primary", "pmid": "31231024", "doi": "10.1016/j.stemcr.2019.05.021", "url": "https://pubmed.ncbi.nlm.nih.gov/31231024/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31231024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC1", "CSC3" ] }, { "n": 53, "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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38206813", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC1", "CSC2" ] }, { "n": 54, "citation": "Lupiáñez DG, Kraft K, Heinrich V et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell. 2015.", "tier": "A", "kind": "primary", "pmid": "25959774", "doi": "10.1016/j.cell.2015.04.004", "url": "https://pubmed.ncbi.nlm.nih.gov/25959774/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25959774", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph15. No complete-paper or supplement audit claimed.", "carries_claims": [ "C54", "CSC2", "CSC3", "CH" ] }, { "n": 55, "citation": "Hyle J, Zhang Y, Wright S et al. Acute depletion of CTCF directly affects MYC regulation through loss of enhancer-promoter looping. Nucleic acids research. 2019.", "tier": "A", "kind": "primary", "pmid": "31127282", "doi": "10.1093/nar/gkz462", "url": "https://pubmed.ncbi.nlm.nih.gov/31127282/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31127282", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC2", "CSC3" ] }, { "n": 56, "citation": "Zhang H, Emerson DJ, Gilgenast TG et al. Chromatin structure dynamics during the mitosis-to-G1 phase transition. Nature. 2019.", "tier": "A", "kind": "primary", "pmid": "31776509", "doi": "10.1038/s41586-019-1778-y", "url": "https://pubmed.ncbi.nlm.nih.gov/31776509/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31776509", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C56", "CSC1", "CSC3" ] }, { "n": 57, "citation": "Nora EP, Lajoie BR, Schulz EG et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22495304", "doi": "10.1038/nature11049", "url": "https://pubmed.ncbi.nlm.nih.gov/22495304/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22495304", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C57", "CSC1", "CSC2" ] }, { "n": 58, "citation": "Schwarzer W, Abdennur N, Goloborodko A et al. Two independent modes of chromatin organization revealed by cohesin removal. Nature. 2017.", "tier": "A", "kind": "primary", "pmid": "29094699", "doi": "10.1038/nature24281", "url": "https://pubmed.ncbi.nlm.nih.gov/29094699/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29094699", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 8:Main text (unsectioned body paragraphs), 0:Disappearance of TADs and peaks, 2:Transcriptional changes upon TAD loss. No complete-paper or supplement audit claimed.", "carries_claims": [ "C58", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 59, "citation": "Willemin A, Lopez-Delisle L, Bolt CC et al. Induction of a chromatin boundary in vivo upon insertion of a TAD border. 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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": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31124784", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph5, 1:Results:paragraph45, 1:Results:paragraph46, 1:Results:paragraph51, 1:Results:paragraph52. 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