{ "$schema_version": "5.3", "review_mode": "revision", "claim_restatement": { "index_wording": "Super-enhancer Model of Cell Identity", "entry_form": "claim", "gradeable_restatement": "Super-enhancers are a functionally distinct regulatory class that disproportionately controls cell-identity genes, rather than a quantitative extension of typical enhancers.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Cell lineage, developmental stage, locus, calling parameters, reference conventional clusters, promoter compatibility and output scale are fixed before outcomes.", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Super-enhancer Model of Cell Identity", "central_claim": "Super-enhancers are a functionally distinct regulatory class that disproportionately controls cell-identity genes, rather than a quantitative extension of typical enhancers.", "proposed_mechanism": "Super-enhancers are a functionally distinct regulatory class that disproportionately controls cell-identity genes, rather than a quantitative extension of typical enhancers.", "claimed_scope": "Mammalian native clusters called by prespecified high-ChIP stitching rules; functional distinction and normal-lineage identity endpoints separated from cancer fitness and expression alone.", "claimed_level": [ "maintenance", "initiation" ], "is_conjunctive": true, "conjunctive_note": "Canonical index weakest-link retained; SC3 adapted from oncogenic necessity to the website cell-identity claim before scoring. Operational calling cannot establish qualitative functional distinction." }, "rubric_routing": { "primary_rubric": "03-epigenetics-gene-regulation.md", "secondary_rubrics": [], "index_notes_applied": [ "Canonical index weakest-link retained; SC3 adapted from oncogenic necessity to the website cell-identity claim before scoring. Operational calling cannot establish qualitative functional distinction." ], "rubric_fit_note": "Rubric03 applies to native transcription and lineage function. SC3 is adapted before scoring from the index oncogenic necessity formulation to the website cell-identity claim; cancer fitness, differentiation and terminal output remain distinct. Operational existence is scored as causal evidence, not denial of the measurable category." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Super-enhancers are operationally distinguishable by reproducible chromatin signal.", "subclaim_type": "existence", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "High-occupancy clusters are reproducibly measured under fixed calling rules and enrich near cell-identity genes. The category is operational; Β marks the causal association boundary, not uncertainty that the signal is observed." }, { "id": "SC2", "statement": "Super-enhancers functionally differ from conventional enhancers beyond additive or hierarchical effects.", "subclaim_type": "mechanism", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Selected clusters exhibit genuine nonadditivity, facilitators, hierarchy and positional effects. However, equally strong conventional elements and dispensable called clusters challenge a qualitative class distinction beyond those local rules. One index-flagged falsification pattern lowers mechanistic Γ to Β; it does not claim all constituents always add independently." }, { "id": "SC3", "statement": "This distinct regulatory class disproportionately controls cell-identity genes.", "subclaim_type": "generalization", "scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "claimed_scope": "Endogenous locus, cell state, temporal resolution and intervention specified before outcomes", "governing_rubric": "03-epigenetics-gene-regulation.md", "key_evidence_anchor": "Original perturbation with functional transcription/architecture and specificity controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Specific native enhancer-cluster deletions affect lineage formation or function, including loss of retinal bipolar cells after Vsx2-region deletion. These establish narrow causal dependencies. The registered SC3 additionally requires that a distinct SE class disproportionately controls identity; activity-matched conventional-cluster contrasts and class-specific mediation are not established, so that broad transfer remains Γ." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "Canonical index weakest-link retained; SC3 adapted from oncogenic necessity to the website cell-identity claim before scoring. Operational calling cannot establish qualitative functional distinction.", "primary_subclaim_id": "SC2", "aggregation_derivation": "The registered weakest-link returns Β from SC1 and SC2. SC1 is a reproducible operational association, not evidence for qualitative causal class distinction. SC2 has local mechanistic plausibility at Γ, but one native class-distinction prediction challenge lowers it to Β: called clusters can be dispensable while conventional elements are strongly required, and additive/hierarchical or facilitator rules explain many effects. Native nonadditivity is retained and a universal additive counterclaim is rejected. SC3 is Γ for the prespecified distinct-class disproportionate identity claim, while individual native lineage dependencies have real context-specific causality.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Β", "scope_matched_would_return": "Β", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M3", "is_nominal": false, "name": "Facilitator grammar and architectural cluster", "core_claim": "Nonactivating elements and their positions support adjacent activators, with local interaction and recruitment rules.", "explains_what_nominal_does_not": "Nonactivating elements and their positions support adjacent activators, with local interaction and recruitment rules.", "strongest_supporting_evidence": [ "Native alpha-globin reconstruction, positional interchange and heterologous beta-globin facilitator rescue." ], "strongest_contradictory_evidence": [ "Facilitators coexist with true local nonadditivity; evidence does not justify asserting that their mechanism excludes synergy." ], "hsef_level_for_this_model": "Ε", "rationale": "Native alpha-globin reconstruction, positional interchange and heterologous beta-globin facilitator rescue. Facilitators coexist with true local nonadditivity; evidence does not justify asserting that their mechanism excludes synergy." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Additive or hierarchical locus control region", "core_claim": "Unequal activators, redundancy, stage dependence and promoter compatibility explain much cluster behavior.", "explains_what_nominal_does_not": "Unequal activators, redundancy, stage dependence and promoter compatibility explain much cluster behavior.", "strongest_supporting_evidence": [ "Native ESC, Wap, Golli/Mbp, Myc and heart perturbations support heterogeneous local hierarchy." ], "strongest_contradictory_evidence": [ "An additive-only universal account fails alpha-globin reconstruction and Fgf5 amplification." ], "hsef_level_for_this_model": "Ε", "rationale": "Native ESC, Wap, Golli/Mbp, Myc and heart perturbations support heterogeneous local hierarchy. An additive-only universal account fails alpha-globin reconstruction and Fgf5 amplification." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Transcriptional-load drug sensitivity", "core_claim": "General coactivator and elongation dependence can make highly active genes drug-sensitive.", "explains_what_nominal_does_not": "General coactivator and elongation dependence can make highly active genes drug-sensitive.", "strongest_supporting_evidence": [ "BET inhibition and degradation separate transcription from contacts; targeted TF loss differs from global CDK loss." ], "strongest_contradictory_evidence": [ "These contrasts do not uniquely quantify transcriptional load as the sole determinant; SE contexts can retain selective sensitivity." ], "hsef_level_for_this_model": "Δ", "rationale": "BET inhibition and degradation separate transcription from contacts; targeted TF loss differs from global CDK loss. These contrasts do not uniquely quantify transcriptional load as the sole determinant; SE contexts can retain selective sensitivity." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "LLPS coactivator condensate", "core_claim": "Multivalent assemblies concentrate machinery and may enhance selected bursts.", "explains_what_nominal_does_not": "Multivalent assemblies concentrate machinery and may enhance selected bursts.", "strongest_supporting_evidence": [ "Coactivator reconstitution and native Sox2 condensate-distance relationships support plausibility." ], "strongest_contradictory_evidence": [ "Liquid-state-specific native rescue is not isolated in examined passages; hubs are rare and broad drugs are pleiotropic." ], "hsef_level_for_this_model": "Γ", "rationale": "Coactivator reconstitution and native Sox2 condensate-distance relationships support plausibility. Liquid-state-specific native rescue is not isolated in examined passages; hubs are rare and broad drugs are pleiotropic." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Emergent-synergy super-enhancer class", "core_claim": "High-ChIP clusters share a distinct nonadditive mechanism that determines identity beyond conventional clusters.", "explains_what_nominal_does_not": "High-ChIP clusters share a distinct nonadditive mechanism that determines identity beyond conventional clusters.", "strongest_supporting_evidence": [ "Native local nonadditivity and meaningful selected developmental dependencies are causal positives." ], "strongest_contradictory_evidence": [ "Local mechanisms and conventional networks explain much of the behavior without a distinct SE class; one class-distinction falsification applies, not a denial of enhancer dependence." ], "hsef_level_for_this_model": "Β", "rationale": "Native local nonadditivity and meaningful selected developmental dependencies are causal positives. Local mechanisms and conventional networks explain much of the behavior without a distinct SE class; one class-distinction falsification applies, not a denial of enhancer dependence." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Blayney separates classical activators from facilitators through native reconstruction and positional rescue. Moorthy finds strong non-SE regions and inactive called SEs; Shin reveals motif-specific hierarchy and additive tested pairs. These favor heterogeneous internal grammar over either a uniformly additive account or a unique class-wide synergy law.", "study_separating_rank1_from_rank2": "Blayney separates classical activators from facilitators through native reconstruction and positional rescue. Moorthy finds strong non-SE regions and inactive called SEs; Shin reveals motif-specific hierarchy and additive tested pairs. These favor heterogeneous internal grammar over either a uniformly additive account or a unique class-wide synergy law.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "23582322", "title": "Master transcription factors and mediator establish super-enhancers at key cell identity genes.", "citation": "Whyte WA, Orlando DA, Hnisz D et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013.", "doi": "10.1016/j.cell.2013.03.035", "pmcid": "PMC3653129", "url": "https://pubmed.ncbi.nlm.nih.gov/23582322/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23582322/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23582322", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph11, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mouse ESC and differentiated cell maps", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "High Mediator domains mark identity genes; factor depletion preferentially reduces their output.", "what_it_does_not_show": "Calling is operational; global factor loss and reporter strength do not isolate class-specific synergy.", "confounders_present": [ "Calling is operational; global factor loss and reporter strength do not isolate class-specific synergy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 2, "pmid": "24119843", "title": "Super-enhancers in the control of cell identity and disease.", "citation": "Hnisz D, Abraham BJ, Lee TI et al. Super-enhancers in the control of cell identity and disease. Cell. 2013.", "doi": "10.1016/j.cell.2013.09.053", "pmcid": "PMC3841062", "url": "https://pubmed.ncbi.nlm.nih.gov/24119843/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24119843/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24119843", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human tissue and mouse ESC maps", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "High occupancy clusters associate with identity and disease loci across tissues.", "what_it_does_not_show": "Nearest-gene assignment and mark enrichment do not establish a functional class or identity necessity.", "confounders_present": [ "Nearest-gene assignment and mark enrichment do not establish a functional class or identity necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 3, "pmid": "25801169", "title": "Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers.", "citation": "Hnisz D, Schuijers J, Lin CY et al. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Molecular cell. 2015.", "doi": "10.1016/j.molcel.2015.02.014", "pmcid": "PMC4402134", "url": "https://pubmed.ncbi.nlm.nih.gov/25801169/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25801169/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25801169", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native mouse ESC constituent deletions", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Prdm14 E3 deletion reduces neighboring acetylation; constituent effects and signaling responses vary.", "what_it_does_not_show": "Single deletions and pathway stimulation do not distinguish emergent class behavior from local hierarchy.", "confounders_present": [ "Single deletions and pathway stimulation do not distinguish emergent class behavior from local hierarchy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 4, "pmid": "27376235", "title": "Genetic dissection of the α-globin super-enhancer in vivo.", "citation": "Hay D, Hughes JR, Babbs C et al. Genetic dissection of the α-globin super-enhancer in vivo. Nature genetics. 2016.", "doi": "10.1038/ng.3605", "pmcid": "PMC5058437", "url": "https://pubmed.ncbi.nlm.nih.gov/27376235/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27376235/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27376235", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:Results:paragraph18, 0:Results:paragraph20, 0:Results:paragraph21, 0:Results:paragraph22, 0:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native mouse alpha-globin allelic series", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Single and two selected double deletions show dominant activators, apparent additivity and retained domain structure.", "what_it_does_not_show": "Later reconstruction reveals interactions missed by this limited deletion series; erythroid expression is not identity conversion.", "confounders_present": [ "Later reconstruction reveals interactions missed by this limited deletion series; erythroid expression is not identity conversion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Shared α-globin lineage/models/laboratory with reconstruction and inversion papers; new alleles are distinct experiments but not independent proof of a class-wide mechanism." ] }, { "n": 5, "pmid": "27895109", "title": "Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes.", "citation": "Moorthy SD, Davidson S, Shchuka VM et al. Enhancers and super-enhancers have an equivalent regulatory role in embryonic stem cells through regulation of single or multiple genes. Genome research. 2017.", "doi": "10.1101/gr.210930.116", "pmcid": "PMC5287230", "url": "https://pubmed.ncbi.nlm.nih.gov/27895109/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27895109/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27895109", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:Results:paragraph7, 0:Results:paragraph11, 0:Results:paragraph12, 0:Results:paragraph17. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native allele-specific mouse ESC deletions", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Strong non-SE enhancers and dispensable called SEs coexist; cluster effects and redundancy vary.", "what_it_does_not_show": "Selected loci and incomplete combinations do not establish every enhancer's equivalence or a universal additive law.", "confounders_present": [ "Selected loci and incomplete combinations do not establish every enhancer's equivalence or a universal additive law." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 6, "pmid": "27376239", "title": "Hierarchy within the mammary STAT5-driven Wap super-enhancer.", "citation": "Shin HY, Willi M, HyunYoo K et al. Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nature genetics. 2016.", "doi": "10.1038/ng.3606", "pmcid": "PMC4963296", "url": "https://pubmed.ncbi.nlm.nih.gov/27376239/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27376239/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27376239", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:RESULTS:paragraph7, 0:RESULTS:paragraph9, 0:RESULTS:paragraph10. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native mammary Wap mouse motif mutants", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Tested pairs are additive; combined proximal TF-site loss prevents cluster assembly and Wap induction.", "what_it_does_not_show": "Motif and stage specificity matter; high milk-gene output is not a whole-lineage identity switch.", "confounders_present": [ "Motif and stage specificity matter; high milk-gene output is not a whole-lineage identity switch." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 7, "pmid": "29507293", "title": "Dissecting super-enhancer hierarchy based on chromatin interactions.", "citation": "Huang J, Li K, Cai W et al. Dissecting super-enhancer hierarchy based on chromatin interactions. Nature communications. 2018.", "doi": "10.1038/s41467-018-03279-9", "pmcid": "PMC5838163", "url": "https://pubmed.ncbi.nlm.nih.gov/29507293/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29507293/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29507293", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph23, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native human K562 hub editing", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Hub repression and deletion disrupt output and neighbor marks more than nonhub deletion; CTCF-site effects are smaller.", "what_it_does_not_show": "Transformed cells and selected clusters do not provide activity-matched conventional-cluster or whole-identity comparisons.", "confounders_present": [ "Transformed cells and selected clusters do not provide activity-matched conventional-cluster or whole-identity comparisons." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [ "Reuses SLC25A37 functional findings from PMID26766440; new MYO1D/SMYD3 perturbations distinguished." ] }, { "n": 8, "pmid": "38101409", "title": "Super-enhancers include classical enhancers and facilitators to fully activate gene expression.", "citation": "Blayney JW, Francis H, Rampasekova A et al. Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell. 2023.", "doi": "10.1016/j.cell.2023.11.030", "pmcid": "PMC10858684", "url": "https://pubmed.ncbi.nlm.nih.gov/38101409/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38101409/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38101409", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph20, 1:RESULTS:paragraph21. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "native alpha-globin reconstruction and mouse validation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Enhancers require interchangeable position-dependent facilitators for full output; reconstructed alleles rescue function.", "what_it_does_not_show": "Erythroid populations retain lineage identity; same-locus platform cannot establish a class-wide distinct mechanism.", "confounders_present": [ "Erythroid populations retain lineage identity; same-locus platform cannot establish a class-wide distinct mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [ "Revalidates and extends α-globin deletion series; the broad locus platform is shared with27376235." ] }, { "n": 9, "pmid": "39863595", "title": "The α-globin super-enhancer acts in an orientation-dependent manner.", "citation": "Kassouf MT, Francis HS, Gosden M et al. The α-globin super-enhancer acts in an orientation-dependent manner. Nature communications. 2025.", "doi": "10.1038/s41467-025-56380-1", "pmcid": "PMC11762767", "url": "https://pubmed.ncbi.nlm.nih.gov/39863595/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39863595/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID40108171" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39863595", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph12, 1:Results:paragraph16. 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Transcriptional regulation and chromatin architecture maintenance are decoupled functions at the Sox2 locus. Genes & development. 2022.", "doi": "10.1101/gad.349489.122", "pmcid": "PMC9296009", "url": "https://pubmed.ncbi.nlm.nih.gov/35710138/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35710138/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35710138", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 0:Results:paragraph4, 0:Results:paragraph7, 0:Results:paragraph11, 0:Results:paragraph17, 0:Results:paragraph18. 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Temporal dissection of an enhancer cluster reveals distinct temporal and functional contributions of individual elements. Molecular cell. 2021.", "doi": "10.1016/j.molcel.2020.12.047", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33482114/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33482114/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33482114", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Transcriptional regulators of the Golli/myelin basic protein locus integrate additive and stealth activities. PLoS genetics. 2020.", "doi": "10.1371/journal.pgen.1008752", "pmcid": "PMC7446974", "url": "https://pubmed.ncbi.nlm.nih.gov/32790717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32790717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32790717", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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The interdependence of mammary-specific super-enhancers and their native promoters facilitates gene activation during pregnancy. Experimental & molecular medicine. 2020.", "doi": "10.1038/s12276-020-0425-x", "pmcid": "PMC7210877", "url": "https://pubmed.ncbi.nlm.nih.gov/32321991/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32321991/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32321991", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart. Circulation research. 2021.", "doi": "10.1161/CIRCRESAHA.120.317045", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33107387/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33107387/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33107387", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Defining Essential Enhancers for Pluripotent Stem Cells Using a Features-Oriented CRISPR-Cas9 Screen. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.108309", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33113365/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33113365/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33113365", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Genome editing demonstrates that the -5 kb Nanog enhancer regulates Nanog expression by modulating RNAPII initiation and/or recruitment. The Journal of biological chemistry. 2021.", "doi": "10.1074/jbc.RA120.015152", "pmcid": "PMC7948488", "url": "https://pubmed.ncbi.nlm.nih.gov/33334884/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33334884/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33334884", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Super-enhancers conserved within placental mammals maintain stem cell pluripotency. Proceedings of the National Academy of Sciences of the United States of America. 2022.", "doi": "10.1073/pnas.2204716119", "pmcid": "PMC9546576", "url": "https://pubmed.ncbi.nlm.nih.gov/36161929/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36161929/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36161929", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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A flexible repertoire of transcription factor binding sites and a diversity threshold determines enhancer activity in embryonic stem cells. Genome research. 2021.", "doi": "10.1101/gr.272468.120", "pmcid": "PMC8015845", "url": "https://pubmed.ncbi.nlm.nih.gov/33712417/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33712417/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33712417", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Enhancer-promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness. Nature genetics. 2023.", "doi": "10.1038/s41588-022-01295-6", "pmcid": "PMC10758292", "url": "https://pubmed.ncbi.nlm.nih.gov/36717694/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36717694/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36717694", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation. Cell reports. 2016.", "doi": "10.1016/j.celrep.2016.04.087", "pmcid": "PMC4899175", "url": "https://pubmed.ncbi.nlm.nih.gov/27239026/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27239026/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27239026", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Progressing super-enhancer landscape during mammary differentiation controls tissue-specific gene regulation. Nucleic acids research. 2018.", "doi": "10.1093/nar/gky891", "pmcid": "PMC6237736", "url": "https://pubmed.ncbi.nlm.nih.gov/30285185/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30285185/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30285185", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic acids research. 2016.", "doi": "10.1093/nar/gkv999", "pmcid": "PMC4756855", "url": "https://pubmed.ncbi.nlm.nih.gov/26446995/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26446995/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26446995", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by regulating the activity of super-enhancers. Nature communications. 2022.", "doi": "10.1038/s41467-022-33333-6", "pmcid": "PMC9500044", "url": "https://pubmed.ncbi.nlm.nih.gov/36138028/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36138028/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36138028", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis. Nature communications. 2021.", "doi": "10.1038/s41467-020-20713-z", "pmcid": "PMC7814021", "url": "https://pubmed.ncbi.nlm.nih.gov/33462242/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33462242/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33462242", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Dynamic Control of Enhancer Repertoires Drives Lineage and Stage-Specific Transcription during Hematopoiesis. Developmental cell. 2016.", "doi": "10.1016/j.devcel.2015.12.014", "pmcid": "PMC4714361", "url": "https://pubmed.ncbi.nlm.nih.gov/26766440/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26766440/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26766440", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Super-enhancer switching drives a burst in gene expression at the mitosis-to-meiosis transition. Nature structural & molecular biology. 2020.", "doi": "10.1038/s41594-020-0488-3", "pmcid": "PMC8690596", "url": "https://pubmed.ncbi.nlm.nih.gov/32895557/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32895557/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32895557", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection. The Journal of experimental medicine. 2021.", "doi": "10.1084/jem.20202512", "pmcid": "PMC8160575", "url": "https://pubmed.ncbi.nlm.nih.gov/34037670/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34037670/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34037670", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Deletion of Mediator 1 suppresses TGFβ signaling leading to changes in epidermal lineages and regeneration. PloS one. 2020.", "doi": "10.1371/journal.pone.0238076", "pmcid": "PMC7455038", "url": "https://pubmed.ncbi.nlm.nih.gov/32857768/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32857768/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32857768", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Vitamin D receptor cross-talk with p63 signaling promotes epidermal cell fate. The Journal of steroid biochemistry and molecular biology. 2023.", "doi": "10.1016/j.jsbmb.2023.106352", "pmcid": "PMC11634282", "url": "https://pubmed.ncbi.nlm.nih.gov/37330071/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37330071/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37330071", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts. Cellular & molecular immunology. 2023.", "doi": "10.1038/s41423-022-00959-x", "pmcid": "PMC9794822", "url": "https://pubmed.ncbi.nlm.nih.gov/36513810/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36513810/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36513810", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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ARID1A safeguards the canalization of the cell fate decision during osteoclastogenesis. Nature communications. 2024.", "doi": "10.1038/s41467-024-50225-z", "pmcid": "PMC11252270", "url": "https://pubmed.ncbi.nlm.nih.gov/39013863/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39013863/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39013863", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Rewiring of 3D chromatin topology orchestrates transcriptional reprogramming in muscle fiber-type specification and transformation. Nature communications. 2025.", "doi": "10.1038/s41467-025-60866-3", "pmcid": "PMC12219728", "url": "https://pubmed.ncbi.nlm.nih.gov/40592831/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40592831/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40592831", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression. Cancer research. 2024.", "doi": "10.1158/0008-5472.CAN-23-3995", "pmcid": "PMC11534545", "url": "https://pubmed.ncbi.nlm.nih.gov/39186674/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39186674/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39186674", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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AP-1 subunits converge promiscuously at enhancers to potentiate transcription. Genome research. 2021.", "doi": "10.1101/gr.267898.120", "pmcid": "PMC8015846", "url": "https://pubmed.ncbi.nlm.nih.gov/33674350/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33674350/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33674350", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Ligand dependent gene regulation by transient ERα clustered enhancers. PLoS genetics. 2020.", "doi": "10.1371/journal.pgen.1008516", "pmcid": "PMC6975561", "url": "https://pubmed.ncbi.nlm.nih.gov/31905229/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31905229/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31905229", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin. Genome research. 2015.", "doi": "10.1101/gr.184986.114", "pmcid": "PMC4381522", "url": "https://pubmed.ncbi.nlm.nih.gov/25677180/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25677180/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25677180", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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A Dynamic Folded Hairpin Conformation Is Associated with α-Globin Activation in Erythroid Cells. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.01.044", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32075757/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32075757/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32075757", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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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": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34197738", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Single-cell 3D genome imaging shows super-enhancer hubs are rare, nonspecific, and neither necessary nor sufficient for transcriptional bursting. Cell genomics. 2026.", "doi": "10.1016/j.xgen.2026.101331", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42607687", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013.", "doi": "10.1016/j.cell.2013.03.036", "pmcid": "PMC3760967", "url": "https://pubmed.ncbi.nlm.nih.gov/23582323/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23582323/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23582323", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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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": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33431820", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph12, 1:Results:paragraph17, 1:Results:paragraph21. 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Role of BRD4 in hematopoietic differentiation of embryonic stem cells. Epigenetics. 2014.", "doi": "10.4161/epi.27711", "pmcid": "PMC4121367", "url": "https://pubmed.ncbi.nlm.nih.gov/24445267/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24445267/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24445267", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function. Circulation. 2020.", "doi": "10.1161/CIRCULATIONAHA.120.047239", "pmcid": "PMC7736324", "url": "https://pubmed.ncbi.nlm.nih.gov/33113340/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33113340/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33113340", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. 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Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. The Journal of biological chemistry. 2012.", "doi": "10.1074/jbc.M112.413047", "pmcid": "PMC3522308", "url": "https://pubmed.ncbi.nlm.nih.gov/23086925/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23086925/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23086925", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "primary human CD4 cells BRD4 inhibition", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "BRD4-associated elongation and lineage output depend on bromodomain interactions.", "what_it_does_not_show": "Enhancer and promoter biochemistry precedes the SE label and is not specific to that classification.", "confounders_present": [ "Enhancer and promoter biochemistry precedes the SE label and is not specific to that classification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 65, "pmid": "33761351", "title": "An interdependent network of functional enhancers regulates transcription and EZH2 loading at the INK4a/ARF locus.", "citation": "Farooq U, Saravanan B, Islam Z et al. An interdependent network of functional enhancers regulates transcription and EZH2 loading at the INK4a/ARF locus. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.108898", "pmcid": "PMC7611173", "url": "https://pubmed.ncbi.nlm.nih.gov/33761351/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33761351/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33761351", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native human INK4a-ARF enhancer network deletion", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Conventional enhancer network is interdependent and can collapse after individual deletion.", "what_it_does_not_show": "Direct comparator in principle, not an activity/number-matched experiment against selected SEs.", "confounders_present": [ "Direct comparator in principle, not an activity/number-matched experiment against selected SEs." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 66, "pmid": "28348365", "title": "Eμ and 3'RR IgH enhancers show hierarchic unilateral dependence in mature B-cells.", "citation": "Saintamand A, Vincent-Fabert C, Marquet M et al. Eμ and 3'RR IgH enhancers show hierarchic unilateral dependence in mature B-cells. Scientific reports. 2017.", "doi": "10.1038/s41598-017-00575-0", "pmcid": "PMC5428668", "url": "https://pubmed.ncbi.nlm.nih.gov/28348365/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28348365/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28348365", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "native mouse IgH regulatory deletion", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Paired regulatory regions show unilateral dependence in mature B cells.", "what_it_does_not_show": "Locus-specific hierarchy and stage dependence do not distinguish emergent synergy from conventional enhancer cooperation.", "confounders_present": [ "Locus-specific hierarchy and stage dependence do not distinguish emergent synergy from conventional enhancer cooperation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 70, "verified": 70, "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": "High-occupancy clusters are reproducibly measured under fixed calling rules and enrich near cell-identity genes. The category is operational; Β marks the causal association boundary, not uncertainty that the signal is observed.", "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": "Specific native enhancer-cluster deletions affect lineage formation or function, including loss of retinal bipolar cells after Vsx2-region deletion. These establish narrow causal dependencies. The registered SC3 additionally requires that a distinct SE class disproportionately controls identity; activity-matched conventional-cluster contrasts and class-specific mediation are not established, so that broad transfer remains Γ.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Super-enhancers are a functionally distinct regulatory class that disproportionately controls cell-identity genes, rather than a quantitative extension of typical enhancers.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Native locus perturbation can establish context-specific causal regulation and lineage consequences without a clinical endpoint. It does not by itself establish a qualitative SE class or disproportionate causal control relative to matched conventional clusters. SC1 descriptive association remains Β; SC2 receives one explicit Γ-to-Β downgrade for the class-distinction prediction challenge. SC3 broad class inference is Γ while retinal and hematopoietic locus-specific causality is preserved separately.", "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": [ "High ChIP intensity and condensate or contact enrichment do not prove a separate functional class.", "Global factor depletion, drug sensitivity, reporter assays and expression alone do not isolate class-specific native identity causality." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "High-occupancy clusters are reproducibly measured under fixed calling rules and enrich near cell-identity genes. The category is operational; Β marks the causal association boundary, not uncertainty that the signal is observed.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "High ChIP intensity and condensate or contact enrichment do not prove a separate functional class.", "Global factor depletion, drug sensitivity, reporter assays and expression alone do not isolate class-specific native identity causality." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Selected clusters exhibit genuine nonadditivity, facilitators, hierarchy and positional effects. However, equally strong conventional elements and dispensable called clusters challenge a qualitative class distinction beyond those local rules. One index-flagged falsification pattern lowers mechanistic Γ to Β; it does not claim all constituents always add independently.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "High ChIP intensity and condensate or contact enrichment do not prove a separate functional class.", "Global factor depletion, drug sensitivity, reporter assays and expression alone do not isolate class-specific native identity causality." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Specific native enhancer-cluster deletions affect lineage formation or function, including loss of retinal bipolar cells after Vsx2-region deletion. These establish narrow causal dependencies. The registered SC3 additionally requires that a distinct SE class disproportionately controls identity; activity-matched conventional-cluster contrasts and class-specific mediation are not established, so that broad transfer remains Γ.", "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 causal transfer beyond the operational category, prespecify an activity-matched cluster panel and test whether the calling category predicts perturbation response beyond signal, length, constituent number and basal output. Operational measurement itself is already 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": "no", "supporting_evidence": [], "what_would_cross_it": "Combinatorial native loss and reconstruction with matched conventional clusters across independently chosen lineages; demonstrate nonadditive interaction terms uniquely predicted by SE classification after activity, spacing, promoter and developmental-state controls." }, { "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": "Local cluster loss and rescue with lineage tracing, single-cell state and physiological function in multiple prespecified normal lineages, comparing equally strong conventional clusters and excluding general growth failure." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Moorthy avoids coding/core-promoter/CTCF-boundary deletions and uses unchanged trans alleles; the null called-SE deletion is tested alongside the required cluster.", "Blayney uses an enhancerless baseline, independently targeted clones, reconstructed WT, motif/accessibility checks and developmentally comparable erythroid populations.", "Shin distinguishes single STAT5 motif loss from combined NFIB/ELF5/STAT5 disruption and uses unaffected mammary control genes.", "Orientation study compares single R2 inversion, full inversion, boundary removal and repositioned promoter deletion with preserved erythroid differentiation.", "Retinal study uses three deletion junction sublines and WT/heterozygote littermates plus independent cellular and functional readouts." ], "note": "Normal mammalian lineage dependence, terminal output and tumor fitness are separate scopes. Locus, stage, calling parameters and promoter compatibility are specified before response. Conserved selected pluripotency elements do not represent all clusters. No responder-defined class is manufactured, and no physiological lineage is inferred solely from a nearby gene name." }, "falsification_patterns_met": [ { "pattern": "Alternative mechanisms explain the phenotype more parsimoniously", "evidence": "For the distinct-class SC2 proposition, native cluster equivalence, inactive called SEs and potent non-SE elements (PMID27895109), additive and hierarchical series (PMID27376235, PMID27376239) and facilitator position grammar (PMID38101409) challenge qualitative class specificity. One downgrade Γ to Β is applied. Native facilitator reconstruction and Fgf5 nonadditivity prevent treating a universal additive-only rival as established.", "subclaim_id": "SC2", "downgrade_applied": true, "from_level": "Γ", "to_level": "Β" } ], "pitfalls_flagged": [ { "pitfall": "Historical deletion result treated as exhaustive", "where": "Hay tested single deletions and two informative doubles; Blayney adds unseen native configurations." }, { "pitfall": "Hierarchy mistaken for synergy absence", "where": "Facilitators and positional grammar can generate nonadditivity; the nominal claim additionally requires class distinction." }, { "pitfall": "Gene expression mistaken for cell identity", "where": "Alpha-globin reconstruction and inversion retain erythroid differentiation despite profound output/hematologic effects." }, { "pitfall": "Consensus mismatches and unsupported absence", "where": "Broad author-name matches and review citations are rejected; unavailable exact targets do not establish no literature exists." }, { "pitfall": "Anatomical phenotype labels reversed", "where": "PMID40592831 abstract assigns conventional EDL/soleus properties in reverse; do not publish those descriptors without original verification." } ], "causal_tally_audit": { "tally_claimed_by_document": 0, "tally_after_audit": 0, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 10, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Shared cohorts, experimental platforms, transgenic lineages and repeated outcomes do not constitute fully independent causal lines." ] }, "steelman": { "case_one_rung_higher": "One rung above, Γ: native facilitator reconstruction, Fgf5 super-additive amplification and retinal lineage deletion clearly exceed mere correlation at selected loci. They motivate a class mechanism, but ordinary enhancer networks also show hierarchy and interdependence, matched class comparisons are missing, and the registered operational SC1 plus class-distinction challenge retain Β for the full conjunction.", "case_one_rung_lower": "One rung below, Α: high-ChIP classification can be circular and broad coactivator drug effects can become a metaphor for causality. However, reproducible cell-state regulatory enrichment, selective native deletions and functional reconstruction provide substantive source support. A single class-distinction falsification is counted once, not repeatedly for every additive or negative paper.", "which_rejected": "Hold overall Β. Local nonlinear regulation and native lineage dependencies are real; the grade attaches to the distinct-class conjunction, not to whether enhancers regulate identity. Neither universal additivity nor universal emergent synergy explains the observed heterogeneous contexts.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Compare a prespecified multi-lineage panel of high-ChIP clusters and conventional clusters matched for constituent number, occupancy, baseline output, spacing and promoter compatibility using native combinatorial deletions and reconstruction with lineage-state tracking." }, "final_score": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "Moderate reflects evidence density and reproducibility, not access depth. Sixty-six primary reports span many laboratories and loci, but on the registered class-distinction question the native perturbation results are heterogeneous and partly opposed: the alpha-globin deletion series is additive with no higher-order effect, called clusters elsewhere range from dispensable to near-essential, strong non-called enhancers exist, facilitator elements are interchangeable rather than class-specific, and the condensate evidence is biochemical with phase specificity unresolved. Few contrasts carry an activity-matched comparator, which is the control the class claim needs. Those are substantive reproducibility and control-design reservations, not gaps in reading access.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered weakest-link returns Β from SC1 and SC2. SC1 is a reproducible operational association, not evidence for qualitative causal class distinction. SC2 has local mechanistic plausibility at Γ, but one native class-distinction prediction challenge lowers it to Β: called clusters can be dispensable while conventional elements are strongly required, and additive/hierarchical or facilitator rules explain many effects. Native nonadditivity is retained and a universal additive counterclaim is rejected. SC3 is Γ for the prespecified distinct-class disproportionate identity claim, while individual native lineage dependencies have real context-specific causality." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Some cluster features arise during differentiation, but state does not solely produce their function (step1). Native deletions and reconstruction establish local dependence (step2). A unique class-wide primary identity switch or rate limit is not established (step3), nor universal necessity of the class rather than selected elements (step4). Demonstrated local clusters amplify output and stabilize specified identity programs (step5).", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent reconstruction, inversion and imaging papers are completed reports; no verified named ongoing class-discriminating experiment is asserted.", "justification": "Recent reconstruction, inversion and imaging papers are completed reports; no verified named ongoing class-discriminating experiment is asserted." }, "stability": { "value": "Stable", "trigger": "No named pending result is asserted to be likely to move the registered score imminently.", "justification": "No named pending result is asserted to be likely to move the registered score imminently." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Β", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": true, "prior_level": "Β", "prior_confidence": "Moderate", "prior_source": "prior-edition/super-enhancer-cell-identity.scorecard.json", "derived_before_consulting_prior": true, "new_level": "Β", "direction": "unchanged", "what_moved_it": "Independent letter lock before prior consultation. Overall weakest-link Β holds; SC2 Γ-to-Β applies one class-specific falsification and SC3 Ε-to-Γ separates class disproportion from selected native lineage causality. Twelve fresh body checks,66 complete abstract/status checks; prior prose preserved outside three blocks with explicit correction log.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Compare a prespecified multi-lineage panel of high-ChIP clusters and conventional clusters matched for constituent number, occupancy, baseline output, spacing and promoter compatibility using native combinatorial deletions and reconstruction with lineage-state tracking.", "readout": "Interaction coefficients for nascent output, single-cell lineage state and physiological function across complete sampled allele series", "critical_control": "Native-position and matched-expression rescue, intact trans alleles, equally active conventional clusters, developmentally matched cells, viability and global transcription", "supporting_result": "SE classification predicts reproducible class-specific nonadditive interactions and functional identity dependence after all matched covariates, with specific rescue", "falsifying_result": "Matched conventional clusters show the same interaction grammar, or effects reduce to local promoter, facilitator, stage or load parameters independently of classification" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Test SEs against activity-, length-, constituent-number- and promoter-matched conventional clusters, rather than weak isolated enhancers.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Use reconstruction and higher-order combinations to avoid missing interactions masked by single deletions.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Separate transcriptional output, physiological specialization, lineage formation and maintenance of cell identity.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Define a nonadditive null model on an explicit output scale, with uncertainty, saturation and promoter limits.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Resolve facilitator position, sequence, promoter compatibility and developmental redundancy across independent loci.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Separate coactivator protein dependence from condensate-phase-specific function and drug pleiotropy.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Audit linked correction bodies for the alpha-globin inversion, Myc cluster, Gasperini screen and Du study before publication; resolve the muscle abstract descriptor inconsistency.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-12", "reviewer": "Codex", "evidence_base_note": "66 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite is queried per case where connected; received tallies/outgoing reference contexts are not audited incoming contrasting statements. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review. Scite monthly quota exhaustion was observed earlier in this batch; no repeated case call or fresh tally/context is claimed. Revision preserves surrounding prior prose; historical count/grade corrections are annotated prominently.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Orthogonal endogenous locus edits, native reconstruction, allele controls, dose/calling stratification and physiological lineage outcomes were considered. These can support higher context-specific local regulation, and upper rungs do not require a clinical RCT. The examined evidence lacks class-matched causal prediction and a distinct common mechanism after controlling activity, number, promoter and stage. This is not re-capping an already convergent same-scope case; the observed convergent local contributions have a narrower scope." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Orthogonal endogenous locus edits, native reconstruction, allele controls, dose/calling stratification and physiological lineage outcomes were considered. These can support higher context-specific local regulation, and upper rungs do not require a clinical RCT. The examined evidence lacks class-matched causal prediction and a distinct common mechanism after controlling activity, number, promoter and stage. This is not re-capping an already convergent same-scope case; the observed convergent local contributions have a narrower scope." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Orthogonal endogenous locus edits, native reconstruction, allele controls, dose/calling stratification and physiological lineage outcomes were considered. These can support higher context-specific local regulation, and upper rungs do not require a clinical RCT. The examined evidence lacks class-matched causal prediction and a distinct common mechanism after controlling activity, number, promoter and stage. This is not re-capping an already convergent same-scope case; the observed convergent local contributions have a narrower scope." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Orthogonal endogenous locus edits, native reconstruction, allele controls, dose/calling stratification and physiological lineage outcomes were considered. These can support higher context-specific local regulation, and upper rungs do not require a clinical RCT. The examined evidence lacks class-matched causal prediction and a distinct common mechanism after controlling activity, number, promoter and stage. This is not re-capping an already convergent same-scope case; the observed convergent local contributions have a narrower scope." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Orthogonal endogenous locus edits, native reconstruction, allele controls, dose/calling stratification and physiological lineage outcomes were considered. These can support higher context-specific local regulation, and upper rungs do not require a clinical RCT. The examined evidence lacks class-matched causal prediction and a distinct common mechanism after controlling activity, number, promoter and stage. This is not re-capping an already convergent same-scope case; the observed convergent local contributions have a narrower scope." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 66, "claims_total": 70, "claims_verified": 70, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 66, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "High Mediator domains mark identity genes; factor depletion preferentially reduces their output. Calling is operational; global factor loss and reporter strength do not isolate class-specific synergy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph5, 1:Results:paragraph11, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "High occupancy clusters associate with identity and disease loci across tissues. Nearest-gene assignment and mark enrichment do not establish a functional class or identity necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph7, 1:RESULTS:paragraph8, 1:RESULTS:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "Prdm14 E3 deletion reduces neighboring acetylation; constituent effects and signaling responses vary. Single deletions and pathway stimulation do not distinguish emergent class behavior from local hierarchy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph3, 1:RESULTS:paragraph4. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Single and two selected double deletions show dominant activators, apparent additivity and retained domain structure. Later reconstruction reveals interactions missed by this limited deletion series; erythroid expression is not identity conversion.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Results:paragraph18, 0:Results:paragraph20, 0:Results:paragraph21, 0:Results:paragraph22, 0:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "Strong non-SE enhancers and dispensable called SEs coexist; cluster effects and redundancy vary. Selected loci and incomplete combinations do not establish every enhancer's equivalence or a universal additive law.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Results:paragraph7, 0:Results:paragraph11, 0:Results:paragraph12, 0:Results:paragraph17. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "Tested pairs are additive; combined proximal TF-site loss prevents cluster assembly and Wap induction. Motif and stage specificity matter; high milk-gene output is not a whole-lineage identity switch.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:RESULTS:paragraph7, 0:RESULTS:paragraph9, 0:RESULTS:paragraph10. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Hub repression and deletion disrupt output and neighbor marks more than nonhub deletion; CTCF-site effects are smaller. Transformed cells and selected clusters do not provide activity-matched conventional-cluster or whole-identity comparisons.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph21, 1:Results:paragraph23, 1:Results:paragraph24, 1:Results:paragraph25. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "Enhancers require interchangeable position-dependent facilitators for full output; reconstructed alleles rescue function. Erythroid populations retain lineage identity; same-locus platform cannot establish a class-wide distinct mechanism.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph4, 1:RESULTS:paragraph5, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 1:RESULTS:paragraph15, 1:RESULTS:paragraph20, 1:RESULTS:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "Cluster inversion redirects output unlike single R2 inversion; boundary and promoter controls exclude simple insulation. Inversion includes genes and positional changes; no block in erythroid differentiation; linked correction body unexamined.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph12, 1:Results:paragraph16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Two key enhancer regions control output while distributed architecture persists; moderate engineered contact loss preserves RNA. Residual contacts remain; snapshot active-site fraction is not directly measured burst frequency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Results:paragraph4, 0:Results:paragraph7, 0:Results:paragraph11, 0:Results:paragraph17, 0:Results:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Cluster loss arrests differentiation; individual modules contribute combinatorially and additively. Original body and linked erratum unexamined; transformation and normal hierarchy are separate scopes.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Time-specific constituent roles and intronic amplifier yield super-additive Fgf5 induction. Expression induction does not uniquely demonstrate a distinct SE class or identity conversion caused by synergy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Single and combined deletions show largely additive effects with lineage-hidden contributions. Shared protein output and lineage context do not isolate class-wide behavior; whole-body text unexamined.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "Native Wap promoter plus enhancer gives much larger induction than enhancer with heterologous promoter. Promoter compatibility explains local synergy; not proof that high-ChIP enhancer clusters are a distinct class.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "Cluster deletion reduces cardiac expression and causes enlarged hearts; promoters compete rather than cooperate. Physiological function is established at selected genes; does not show loss of cardiomyocyte identity or universal synergy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "Selected native enhancers support self-renewal and pluripotency through defined target pathways. Screen hits include CREs without unique SE architecture; growth and identity endpoints require separation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Native enhancer regulates polymerase recruitment or initiation with orientation/distance tests. One enhancer's contribution does not demonstrate emergent cluster synergy distinct from conventional enhancers.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Conserved selected SE disruptions impair pluripotency; reporter activity tracks pluripotent state. Three selected conserved loci do not generalize all clusters; BRD4 is a broad coactivator.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "TF-binding diversity supports strong enhancer activity with some master motifs dispensable. Sequence-complexity threshold is not a unique super-enhancer mechanism; synthetic behavior is scope-limited.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "Strong clusters overcome barriers in epiblast/neural tissues; foregut loss yields specific phenotype. Boundary resistance and cell-state dependence do not establish a class-specific emergent identity code.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Active and inactive enhancers cooperate in local and long-range lineage-specific regulation. Cooperation is broader than high-ChIP classification; no matched class-wide synergy comparison.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "Pregnancy seed enhancer becomes dispensable during lactation, revealing stage-specific compensation. Related Wap platform; distinct developmental output does not establish fixed cluster-class logic.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "Local enhancer loss lowers mammary Stat5 and lineage-dependent transcription. Single feedback enhancer and global downstream signaling do not isolate SE-specific identity necessity.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "SATB1 loss changes DP identity alongside reduced SE activity and contacts. Organizer loss alters many features; local cluster causal specificity is not isolated.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "RUNX1 and SMAD3 depletion switches corneal cells toward epidermal-like programs. Core TF dependence and chromatin changes do not isolate super-enhancer state as the unique mediator.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "Constituent hierarchy and opposing enhancer roles accompany lineage-specific transcription. SLC25A37 findings are reused in Huang; not independent replication of that same locus.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "MyoD-FoxO3 cooperation organizes Myogenin hotspots during differentiation. Shared factor function and selected cluster do not establish an emergent class beyond hierarchy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "A-MYB and SCML2 regulate stage-specific SE landscape and meiotic gene induction. Global regulators and changing cell composition do not isolate individual cluster synergy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "Enhancer occupancy and histone states change with differentiation and metabolic programs. Mapping and temporal covariation alone do not establish causal enhancer-class distinction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "BRD4 perturbations impair effector differentiation and maintenance alongside enhancer activity. Broad protein dependency is not selective SE disruption; immune state outcomes do not isolate cluster architecture.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "Med1 loss changes TGF-beta signaling, epidermal lineages and regeneration. Mediator has broad functions; pathway phenocopy does not establish SE-specific mechanism.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "Vdr loss impairs interfollicular regeneration while preserving sebaceous repopulation. SE colocalization and TF cross-talk do not isolate enhancer-class causal mediation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "Selected enhancer RNAs and BATF affect NFATc1 expression and osteoclast differentiation. RNA and BET effects do not separate cluster architecture from transcription chemistry or broad factor action.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "ARID1A and BRD9 antagonism affects differentiation and associated coactivator assemblies. Broad remodeler loss cannot uniquely establish liquid-state necessity or a separate SE class.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "Tissue-specific enhancer networks and STARD7 pathway activity associate with fiber-state changes. Abstract reverses conventional EDL/soleus fiber descriptors; anatomical identities need original-text verification before publication.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Three deletion sublines lack bipolar neurons with functional visual deficits and preserved gross retinal size. Local developmental necessity does not establish class-wide emergent synergy; local rescue not shown in examined passages.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:RESULTS:paragraph15, 1:RESULTS:paragraph16, 1:RESULTS:paragraph17, 1:RESULTS:paragraph18. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "Stimulus and lineage TFs redeploy at remodeled enhancers during acute induction. Primed versus de novo enhancer effects do not define a unique high-ChIP functional class.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "PRRX1 changes expression and SE landscapes between mesenchymal and adrenergic states. Transcription-factor sufficiency and tumor heterogeneity do not isolate class-specific enhancer-state causality.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "Local enhancer gains and editing contribute to a neural-crest-like tumor state. Cancer genotype and broad drugs limit transfer to normal identity and emergent class distinction.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "Targeted TF degradation disrupts autoregulation more selectively than global transcriptional CDK inhibition. Protein specificity is not a selective liquid-state or enhancer-class intervention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "One MYC regulatory element is required in thymocyte development and induced leukemia. Single enhancer within a broad region does not prove unique class mechanics; cancer and normal outcomes differ.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "Predicted master regulators lack reciprocal circuit dependencies; the fusion protein dominates the state. Tumor-specific hierarchy is not a universal refutation of enhancer functions in normal identity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "Enhancer profiling identifies dependencies whose inhibition reduces tumor growth. Drug and target-gene dependence do not isolate enhancer-class synergy or normal-lineage identity determination.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "A MYC-associated constituent deletion or repression lowers MYC and oncogenic growth. Amplification changes dose; transformation dependence is a separate scope from normal identity and class distinction.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "Local PODXL enhancer and eRNA loss reduce output, migration and xenograft growth. Selected cancer enhancer dependence is not class-wide emergent synergy or normal cell-state conversion.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Fitness enhancers have activating and repressive modules and context-specific accessibility. Fitness is not lineage identity; enhancer modularity extends beyond the SE label.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "Large-scale native screens link many distal elements to target output. Original method-plus-results report; broad repression may spread, and random combinations do not prove SE-wide synergy; erratum unread.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "AP-1 hotspots predict lineage expression and signal response better than SE calls in tested analyses. Predictive comparison is not enhancer-class causality; shared factor recruitment remains a rival.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "Ligand-dependent clustered enhancers control target output independently of called acetylation SEs. Transient signal response differs from persistent identity; local condensate association does not prove liquid-state causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Peak-breadth domains predict identity genes well; local dissections reveal roles obscured by SE calling. Alternative feature stratification does not identify one universal mechanistic class.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Cohesin, condensin II and NIPBL enrich at SEs with associated transcription sensitivity. Complex depletion has architecture and cell-cycle effects; class-specific mechanism not isolated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "Loss weakens spatial enhancer clustering while chromatin marks and enhancer transcription persist. Broad cohesin effects and nearby expression changes do not uniquely prove high-ChIP cluster necessity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Domain formation persists without major enhancer interactions; internal contacts change. Same alpha-globin lineage platform; formation of a domain does not establish class-specific output mechanism.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Original computational predictions and structural data support a folded active-domain arrangement. Original model-plus-measurement research, not independent causal proof of thermodynamic phase separation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Enhancer activation and extrusion trajectory are separable from paused boundary loops. Architecture and biochemical recruitment interact; selected locus does not define a separate enhancer class.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "BRD4 and MED1 assemblies and isolated domains support condensate plausibility. Chemical dissolution and in vitro droplets do not isolate native liquid-state necessity or unique SE class.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C57", "text": "Nearby condensates predict enhanced bursting while basal bursts remain when distant. Spatial predictor is not isolated condensate-phase causality; linked correction body unexamined.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C58", "text": "Multiway SE hubs are rare, promiscuous and not a necessary burst configuration. Fixed snapshots do not test every pairwise interaction or disprove all local constituent cooperation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C59", "text": "Conserved, hierarchical and de novo clusters have distinct trajectories and constituent dependencies. Population heterogeneity and selected deletions do not prove shared emergent class identity mechanics.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C60", "text": "BET inhibition preferentially reduces enhancer-associated oncogene output in tested tumor cells. Global coactivator and elongation effects can explain sensitivity without unique enhancer-class architecture.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C61", "text": "Output changes rapidly despite retained promoter contacts after inhibitor and degrader treatments. Broad chemistry and residual proteins remain; hexanediol is nonspecific and cannot uniquely test liquid state.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph12, 1:Results:paragraph17, 1:Results:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C62", "text": "BRD4 disruption impairs hematoendothelial potential without spontaneous ESC differentiation. Broad protein dependence and partly MYC-independent effects are not selective SE causality.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C63", "text": "Genetic protein loss causes cardiac mitochondrial dysfunction unlike beneficial inhibitor results. Deletion and bromodomain inhibition test different functions; neither uniquely identifies SE architecture.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C64", "text": "BRD4-associated elongation and lineage output depend on bromodomain interactions. Enhancer and promoter biochemistry precedes the SE label and is not specific to that classification.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C65", "text": "Conventional enhancer network is interdependent and can collapse after individual deletion. Direct comparator in principle, not an activity/number-matched experiment against selected SEs.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C66", "text": "Paired regulatory regions show unilateral dependence in mature B cells. Locus-specific hierarchy and stage dependence do not distinguish emergent synergy from conventional enhancer cooperation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "High-occupancy clusters are reproducibly measured under fixed calling rules and enrich near cell-identity genes. The category is operational; Β marks the causal association boundary, not uncertainty that the signal is observed.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 5, 18, 24, 28, 29, 35, 36, 37, 38, 43, 48, 50, 51, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "Selected clusters exhibit genuine nonadditivity, facilitators, hierarchy and positional effects. However, equally strong conventional elements and dispensable called clusters challenge a qualitative class distinction beyond those local rules. One index-flagged falsification pattern lowers mechanistic Γ to Β; it does not claim all constituents always add independently.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 26, 27, 33, 34, 39, 40, 42, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "Specific native enhancer-cluster deletions affect lineage formation or function, including loss of retinal bipolar cells after Vsx2-region deletion. These establish narrow causal dependencies. The registered SC3 additionally requires that a distinct SE class disproportionately controls identity; activity-matched conventional-cluster contrasts and class-specific mediation are not established, so that broad transfer remains Γ.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 50, 51, 52, 55, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Super-enhancer labels identify many important regulatory regions, but native perturbations favor heterogeneous local grammar over a uniquely distinct cell-identity control class.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5, 6, 8, 36, 61 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Whyte WA, Orlando DA, Hnisz D et al. 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Molecular cell. 2021.", "tier": "A", "kind": "primary", "pmid": "34197738", "doi": "10.1016/j.molcel.2021.06.008", "url": "https://pubmed.ncbi.nlm.nih.gov/34197738/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34197738", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C55", "CSC2", "CSC3" ] }, { "n": 56, "citation": "Sabari BR, Dall'Agnese A, Boija A et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science (New York, N.Y.). 2018.", "tier": "A", "kind": "primary", "pmid": "29930091", "doi": "10.1126/science.aar3958", "url": "https://pubmed.ncbi.nlm.nih.gov/29930091/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID29930091", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C56", "CSC2" ] }, { "n": 57, "citation": "Du M, Stitzinger SH, Spille JH et al. Direct observation of a condensate effect on super-enhancer controlled gene bursting. Cell. 2024.", "tier": "A", "kind": "primary", "pmid": "38194964", "doi": "10.1016/j.cell.2023.12.005", "url": "https://pubmed.ncbi.nlm.nih.gov/38194964/", "status_flags": [ "ErratumIn: PMID38614098" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38194964", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C57", "CSC2", "CSC3" ] }, { "n": 58, "citation": "Le DJ, Hafner A, Raja Venkatesh A et al. Single-cell 3D genome imaging shows super-enhancer hubs are rare, nonspecific, and neither necessary nor sufficient for transcriptional bursting. Cell genomics. 2026.", "tier": "A", "kind": "primary", "pmid": "42607687", "doi": "10.1016/j.xgen.2026.101331", "url": "https://pubmed.ncbi.nlm.nih.gov/42607687/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42607687", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C58", "CSC2", "CSC3" ] }, { "n": 59, "citation": "Kai Y, Li BE, Zhu M et al. Mapping the evolving landscape of super-enhancers during cell differentiation. Genome biology. 2021.", "tier": "A", "kind": "primary", "pmid": "34526084", "doi": "10.1186/s13059-021-02485-x", "url": "https://pubmed.ncbi.nlm.nih.gov/34526084/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34526084", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C59", "CSC1", "CSC2", "CSC3" ] }, { "n": 60, "citation": "Lovén J, Hoke HA, Lin CY et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013.", "tier": "A", "kind": "primary", "pmid": "23582323", "doi": "10.1016/j.cell.2013.03.036", "url": "https://pubmed.ncbi.nlm.nih.gov/23582323/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23582323", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC2", "CSC3" ] }, { "n": 61, "citation": "Crump NT, Ballabio E, Godfrey L et al. BET inhibition disrupts transcription but retains enhancer-promoter contact. Nature communications. 2021.", "tier": "A", "kind": "primary", "pmid": "33431820", "doi": "10.1038/s41467-020-20400-z", "url": "https://pubmed.ncbi.nlm.nih.gov/33431820/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33431820", "access_depth": "full_text_partial", "access_note": "Complete original abstract and linked-status metadata freshly examined. Selected body sections: 1:Results:paragraph7, 1:Results:paragraph12, 1:Results:paragraph17, 1:Results:paragraph21. No complete-paper or supplement audit claimed.", "carries_claims": [ "C61", "CSC2", "CSC3", "CH" ] }, { "n": 62, "citation": "Rodriguez RM, Suarez-Alvarez B, Salvanés R et al. Role of BRD4 in hematopoietic differentiation of embryonic stem cells. Epigenetics. 2014.", "tier": "A", "kind": "primary", "pmid": "24445267", "doi": "10.4161/epi.27711", "url": "https://pubmed.ncbi.nlm.nih.gov/24445267/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24445267", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C62", "CSC3" ] }, { "n": 63, "citation": "Kim SY, Zhang X, Schiattarella GG et al. Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function. Circulation. 2020.", "tier": "A", "kind": "primary", "pmid": "33113340", "doi": "10.1161/CIRCULATIONAHA.120.047239", "url": "https://pubmed.ncbi.nlm.nih.gov/33113340/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33113340", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC3" ] }, { "n": 64, "citation": "Zhang W, Prakash C, Sum C et al. Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. The Journal of biological chemistry. 2012.", "tier": "A", "kind": "primary", "pmid": "23086925", "doi": "10.1074/jbc.M112.413047", "url": "https://pubmed.ncbi.nlm.nih.gov/23086925/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID23086925", "access_depth": "abstract_metadata", "access_note": "Complete original abstract and linked-status metadata freshly examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C64", "CSC2", "CSC3" ] }, { "n": 65, "citation": "Farooq U, Saravanan B, Islam Z et al. An interdependent network of functional enhancers regulates transcription and EZH2 loading at the INK4a/ARF locus. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C66", "CSC2", "CSC3" ] } ], "independence_basis": { "required": false, "lines": [ { "label": "Native reconstruction", "sources": [ 8 ], "excludes_error": "Reinsertions and positional swaps distinguish intact-locus loss from direct enhancer and facilitator functions; mouse and ESC-derived erythroid systems remain related." }, { "label": "Native allelic comparator", "sources": [ 5 ], "excludes_error": "Unchanged trans allele and strong non-SE elements separate local regulation from global differentiation and the calling label." }, { "label": "Native lineage function", "sources": [ 36 ], "excludes_error": "Three deletion sublines, single-cell profiles, immunostaining, electron microscopy and vision separate RNA-only change from a genuine developmental consequence; readouts share the deletion cause." } ], "shared_failure_mode_checked": true, "note": "Different assay classes address different errors but do not converge on a unique class-wide mechanism. Related alpha-globin and Wap papers are grouped rather than counted as independent confirmations." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/super-enhancers-functional-synergy/P9gOfRtqQUSSKDtMvMiU4Q/" ], "query_record_note": "Exact visible question/response retained privately in raw browser receipt.", "primary_comparison_count": 9, "primary_comparisons": [ { "pmid": "27376235", "doi": "10.1038/ng.3605", "source_type": "primary study report", "study_group": "PMID27376235", "access_depth": "full_text_partial", "consensus_aspect": "Native apparent additivity is scoped to the tested allele series", "result_comparison": "The original alpha-globin Results agree with Consensus's targeted summary of apparent additive contributions and dominant R1/R2 elements. Single deletions and two informative double deletions do not exhaust all interactions. The broad provider matrix incorrectly reported no additive-deletion papers despite this experimental paper.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27376235/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\27376235-s0-p18-20-21-22-25.json" ] }, { "pmid": "27895109", "doi": "10.1101/gr.210930.116", "source_type": "primary study report", "study_group": "PMID27895109", "access_depth": "full_text_partial", "consensus_aspect": "Called super-enhancers and strong conventional comparators", "result_comparison": "Original allele-specific deletion Results confirm a dispensable called Med13l super-enhancer and strong non-SE Lifr/Jarid2 regions. Consensus's targeted summary accurately identifies functional heterogeneity and the transcription endpoint. Selected comparators are not a complete panel matched on signal, length, element number and promoter compatibility.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27895109/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\27895109-s0-p7-11-12-17.json" ] }, { "pmid": "27376239", "doi": "10.1038/ng.3606", "source_type": "primary study report", "study_group": "PMID27376239", "access_depth": "full_text_partial", "consensus_aspect": "Wap hierarchy does not reduce to either universal synergy or universal addition", "result_comparison": "The original tested enhancer pairs were additive, and combined TF-site loss at the proximal element prevented other components from assembling. Consensus's targeted answer agrees with this distinction. The endpoint is milk-gene expression and stage-dependent regulatory assembly, not conversion of the whole mammary lineage identity.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27376239/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\27376239-s0-p7-9-10.json" ] }, { "pmid": "38101409", "doi": "10.1016/j.cell.2023.11.030", "source_type": "primary study report", "study_group": "PMID38101409", "access_depth": "full_text_partial", "consensus_aspect": "Missing native reconstruction changes the additive interpretation", "result_comparison": "Consensus could not retrieve Blayney's exact paper, whose canonical final publication is 2023. Original reconstruction shows R2 alone produces much less globin than predicted from its single deletion, with position-dependent interchangeable facilitators and matched erythroid populations. This is genuine local functional cooperation and rejects an all-additive counterclaim; it does not establish a qualitatively distinct SE class or an erythroid identity switch.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/38101409/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\38101409-s1-p4-5-13-14-15-20-21.json" ] }, { "pmid": "29507293", "doi": "10.1038/s41467-018-03279-9", "source_type": "primary study report", "study_group": "PMID29507293", "access_depth": "full_text_partial", "consensus_aspect": "Provider absence does not erase hub perturbation evidence", "result_comparison": "Consensus had no original Results for the exact Huang paper. The original hub deletion and nonhub/CTCF-site contrasts show stronger effects of hub removal on selected output and neighboring chromatin marks in K562 cells. It is a native hierarchy experiment in transformed cells, not class-wide identity mediation against fully matched conventional clusters.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/29507293/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\29507293-s1-p21-23-24-25.json" ] }, { "pmid": "39863595", "doi": "10.1038/s41467-025-56380-1", "source_type": "primary study report", "study_group": "PMID39863595", "access_depth": "full_text_partial", "consensus_aspect": "Cluster orientation and correction limits", "result_comparison": "Consensus could not retrieve the exact orientation paper. Original Results show that inverting the cluster changes globin and upstream gene output while erythroid differentiation is retained; isolated R2 inversion and boundary controls narrow alternatives. A linked correction is recorded in original metadata, but its detailed body was not examined. This comparison must not imply that the correction itself was validated.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/39863595/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\39863595-s1-p4-6-8-12-16.json" ] }, { "pmid": "35710138", "doi": "10.1101/gad.349489.122", "source_type": "primary study report", "study_group": "PMID35710138", "access_depth": "full_text_partial", "consensus_aspect": "Native Sox2 chemistry and architecture can separate", "result_comparison": "Consensus had no original exact-paper text. Original allele-specific motif and CTCF-insertion Results separate large transcriptional effects from distributed architecture and show moderate contact reduction without a detected expression change. Residual contacts remain; snapshot active-site fractions do not directly measure live burst frequency.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35710138/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-0-22-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\35710138-s0-p4-7-11-17-18.json" ] }, { "pmid": "33431820", "doi": "10.1038/s41467-020-20400-z", "source_type": "primary study report", "study_group": "PMID33431820", "access_depth": "full_text_partial", "consensus_aspect": "Drug effects on output differ from contact maintenance", "result_comparison": "Consensus could not assess the exact Crump paper. Original short-treatment nascent RNA and Capture-C Results show transcriptional changes while most enhancer-promoter contacts remain, after BET inhibitor and degrader treatments. Drug/protein pleiotropy and nonspecific hexanediol effects prevent interpreting this as a selective SE-phase intervention.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/33431820/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-44-66-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\33431820-s1-p7-12-17-21.json" ] }, { "pmid": "31493975", "doi": "10.1016/j.neuron.2019.08.002", "source_type": "primary study report", "study_group": "PMID31493975", "access_depth": "full_text_partial", "consensus_aspect": "A genuine developmental cell-identity positive", "result_comparison": "Original Vsx2-region deletion removes bipolar cells across three mouse sublines, with single-cell, histological, ultrastructural and visual-function readouts. This strengthens the local identity evidence beyond the provider's mainly expression-based coverage. It does not by itself establish disproportionate causal control by a qualitatively distinct class compared with equally strong conventional enhancers.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/31493975/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\examinations\\original-22-44-6500.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\body-presentation-receipts\\31493975-s1-p15-16-17-18.json" ] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_16_19_2026-10-12\\super-enhancer-cell-identity\\consensus-browser-2026-10-12.json", "sha256": "935f3ebb2897e25942fd1e274971d127cf07b343cb1ea8c70bb1fbb937e14a15" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T20:10:07.324629+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }