{
  "$schema_version": "5.3",
  "review_mode": "fresh",
  "claim_restatement": {
    "index_wording": "Histone Code Hypothesis",
    "entry_form": "phenomenon",
    "gradeable_restatement": "Specific combinations of histone modifications are read as a combinatorial code that causally specifies transcriptional outputs beyond the effects of individual marks.",
    "restatement_required": true,
    "split_into": [],
    "parent_claim": null,
    "scope_qualifiers": [
      {
        "qualifier": "Histone residue/combination, reader architecture, endogenous locus and baseline cell state",
        "determinable_before_outcome": true,
        "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.",
        "action": "retained"
      }
    ]
  },
  "hypothesis": {
    "name": "Histone Code Hypothesis",
    "central_claim": "Specific combinations of histone modifications are read as a combinatorial code that causally specifies transcriptional outputs beyond the effects of individual marks.",
    "proposed_mechanism": "Specific combinations of histone modifications are read as a combinatorial code that causally specifies transcriptional outputs beyond the effects of individual marks.",
    "claimed_scope": "Endogenous loci and cell states specified before outcome; emergent combinations beyond additive individual-mark effects, rather than the existence or function of histone modifications.",
    "claimed_level": [
      "mechanism"
    ],
    "is_conjunctive": true,
    "conjunctive_note": "Use the index combinatorial form and SC3 gate. Individual-mark function and reproducible mark-state association are distinct, stronger or weaker scopes and cannot establish emergent combinatorial instruction."
  },
  "rubric_routing": {
    "primary_rubric": "03-epigenetics-gene-regulation.md",
    "secondary_rubrics": [],
    "index_notes_applied": [
      "Use the index combinatorial form and SC3 gate. Individual-mark function and reproducible mark-state association are distinct, stronger or weaker scopes and cannot establish emergent combinatorial instruction."
    ],
    "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results."
  },
  "subclaim_matrix": {
    "subclaims": [
      {
        "id": "SC1",
        "statement": "Histone modifications correlate reproducibly with transcriptional states.",
        "subclaim_type": "existence",
        "scope": "prespecified loci and cell states",
        "claimed_scope": "prespecified loci and cell states",
        "governing_rubric": "03-epigenetics-gene-regulation.md",
        "key_evidence_anchor": "Genome-wide mark-state association",
        "hsef_level": "Β",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Genome-wide and single-nucleosome patterns reproducibly track transcription and developmental state (PMID16630819,27151869,17997276,16122352). This existence subclaim is supported by association, with continuous gradients and asymmetric nucleosomes limiting discrete-state interpretations; association alone is Β."
      },
      {
        "id": "SC2",
        "statement": "Individual histone marks causally contribute to specific transcriptional outputs.",
        "subclaim_type": "mechanism",
        "scope": "mark and locus defined before outcome",
        "claimed_scope": "mark and locus defined before outcome",
        "governing_rubric": "03-epigenetics-gene-regulation.md",
        "key_evidence_anchor": "Mark-specific locus perturbation and functional restoration",
        "hsef_level": "Ζ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Individual-mark/reader pathways causally regulate specified outputs across independently tested systems: Set2/Rpd3S suppresses cryptic initiation (PMID16286007,16286008), endogenous MLL2 catalytic mutation with targeted mark restoration changes selected genes (PMID38724747), and acute COMPASS loss with KDM5 buffering affects pause-release (PMID36859550). Orthogonal genetics, biochemical specificity and direct RNA outcomes exclude pure association. Contexts and residual/noncatalytic effects are mapped, supporting Ζ but not all-locus/state Η."
      },
      {
        "id": "SC3",
        "statement": "Histone-mark combinations causally encode outputs beyond additive individual-mark effects.",
        "subclaim_type": "mechanism",
        "scope": "endogenous loci, reader architecture and cell state defined before outcome",
        "claimed_scope": "endogenous loci, reader architecture and cell state defined before outcome",
        "governing_rubric": "03-epigenetics-gene-regulation.md",
        "key_evidence_anchor": "Factorial mark perturbation, combination-specific readout and reader rescue",
        "hsef_level": "Γ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "BPTF dual-mark recognition and binding mutants are real, but tagged localization is not transcriptional necessity (PMID21596426). TRIM33 loss/PHD rescue establishes contextual reader dependence, without independently factorially editing endogenous K9/K18 marks (PMID22196728). Paired Polycomb targeting increases reporter silencing with at least additive and potentially synergistic effects (PMID38724747); the combination arm remains reporter-based. NURF writer deletions/truncations test recruitment, whereas full Nurf301 deletion tests transcription, leaving the exact combination-to-output bridge unresolved (PMID42165139). KAT6B loss after bivalent-specific recruitment is also a protein-function test, not factorial mark necessity (PMID39731917). Therefore Δ for the registered emergent endogenous code is not yet crossed."
      }
    ],
    "aggregation_rule": "scope-matched",
    "aggregation_preregistered": true,
    "aggregation_rationale": "Use the index combinatorial form and SC3 gate. Individual-mark function and reproducible mark-state association are distinct, stronger or weaker scopes and cannot establish emergent combinatorial instruction.",
    "primary_subclaim_id": "SC3",
    "aggregation_derivation": "The preregistered SC3 gate returns Γ. Structural recognition, cellular recruitment and engineered reporter combinations make the mechanism plausible, while direct endogenous factorial mark dependence beyond individual effects remains unresolved. This is not a refutation of histone function: SC2 reaches Ζ on independent mark/reader perturbations with functional outcomes, and the observational SC1 stays Β on its own evidence class. Recent bivalent-reader and NURF results are included rather than inheriting the index grade uncritically.",
    "aggregation_alternatives": {
      "weakest_link_would_return": "Β",
      "primary_subclaim_would_return": "Γ",
      "scope_matched_would_return": "Γ",
      "note": "Separate narrow successes do not replace the preregistered gate."
    },
    "index_rule_deviation": ""
  },
  "competing_models": {
    "models_evaluated": [
      {
        "rank_in_tournament": 1,
        "model_id": "M2",
        "is_nominal": false,
        "name": "Context-defined individual-mark functions",
        "core_claim": "Individual marks and recruited factors tune transcription at selected loci rather than encoding a universal vocabulary.",
        "explains_what_nominal_does_not": "Individual marks and recruited factors tune transcription at selected loci rather than encoding a universal vocabulary.",
        "strongest_supporting_evidence": [
          "Endogenous MLL2/KDM5/Set2 and direct RNA endpoints support causal action (PMID38724747,36859550,16286007)."
        ],
        "strongest_contradictory_evidence": [
          "Some combinations enhance recruitment, so completely independent mark action is too simple."
        ],
        "hsef_level_for_this_model": "Ζ",
        "rationale": "Endogenous MLL2/KDM5/Set2 and direct RNA endpoints support causal action (PMID38724747,36859550,16286007). Some combinations enhance recruitment, so completely independent mark action is too simple."
      },
      {
        "rank_in_tournament": 2,
        "model_id": "M3",
        "is_nominal": false,
        "name": "Reader-writer feedback and state stabilization",
        "core_claim": "Multivalent readers and writer feedback stabilize states initiated by sequence factors and signaling.",
        "explains_what_nominal_does_not": "Multivalent readers and writer feedback stabilize states initiated by sequence factors and signaling.",
        "strongest_supporting_evidence": [
          "TRIM33/Smad/p300, EED feedback and NURF recruitment support context-dependent circuitry (PMID22196728,19767730,42165139)."
        ],
        "strongest_contradictory_evidence": [
          "Protein-state feedback does not uniquely explain every sequence-specific response or establish one material-state mechanism."
        ],
        "hsef_level_for_this_model": "Ε",
        "rationale": "TRIM33/Smad/p300, EED feedback and NURF recruitment support context-dependent circuitry (PMID22196728,19767730,42165139). Protein-state feedback does not uniquely explain every sequence-specific response or establish one material-state mechanism."
      },
      {
        "rank_in_tournament": 3,
        "model_id": "M1",
        "is_nominal": true,
        "name": "Strict combinatorial instruction",
        "core_claim": "Specific mark combinations encode emergent transcription outputs beyond constituent effects.",
        "explains_what_nominal_does_not": "Specific mark combinations encode emergent transcription outputs beyond constituent effects.",
        "strongest_supporting_evidence": [
          "BPTF, TRIM33 and bivalent/KAT6B recognition plus controlled paired reporter effects are a serious steelman (PMID21596426,22196728,39731917,38724747)."
        ],
        "strongest_contradictory_evidence": [
          "A native-locus factorial readout with combination-selective rescue remains missing; H3K27ac loss, cumulative H4 effects and the failed TAF3 switch contradict simple code extrapolations."
        ],
        "hsef_level_for_this_model": "Γ",
        "rationale": "BPTF, TRIM33 and bivalent/KAT6B recognition plus controlled paired reporter effects are a serious steelman (PMID21596426,22196728,39731917,38724747). A native-locus factorial readout with combination-selective rescue remains missing; H3K27ac loss, cumulative H4 effects and the failed TAF3 switch contradict simple code extrapolations."
      },
      {
        "rank_in_tournament": 4,
        "model_id": "M4",
        "is_nominal": false,
        "name": "Cumulative acetylation and charge effects",
        "core_claim": "Some acetylation effects follow total charge/accessibility rather than site-combination identity.",
        "explains_what_nominal_does_not": "Some acetylation effects follow total charge/accessibility rather than site-combination identity.",
        "strongest_supporting_evidence": [
          "Factorial H4 mutants show cumulative K5/K8/K12 effects versus special K16 behavior (PMID15795371); H3.3K27R retains other acetylations (PMID32085783)."
        ],
        "strongest_contradictory_evidence": [
          "Does not explain methyl-reader specificity and H4K16-specific binding; chemistry of arginine substitutions also differs from selective deacetylation."
        ],
        "hsef_level_for_this_model": "Ε",
        "rationale": "Factorial H4 mutants show cumulative K5/K8/K12 effects versus special K16 behavior (PMID15795371); H3.3K27R retains other acetylations (PMID32085783). Does not explain methyl-reader specificity and H4K16-specific binding; chemistry of arginine substitutions also differs from selective deacetylation."
      },
      {
        "rank_in_tournament": 5,
        "model_id": "M5",
        "is_nominal": false,
        "name": "Transcriptional consequence and metabolic readout",
        "core_claim": "Some marks record ongoing transcription or metabolic context instead of independently instructing it.",
        "explains_what_nominal_does_not": "Some marks record ongoing transcription or metabolic context instead of independently instructing it.",
        "strongest_supporting_evidence": [
          "H2Bub follows Pol II advance and many mark conversions are uncoupled from RNA changes (PMID25049226,17997276)."
        ],
        "strongest_contradictory_evidence": [
          "A universal downstream-only account is contradicted by mark-specific loss/restoration and acute RNA effects (PMID38724747,36859550)."
        ],
        "hsef_level_for_this_model": "Β",
        "rationale": "H2Bub follows Pol II advance and many mark conversions are uncoupled from RNA changes (PMID25049226,17997276). A universal downstream-only account is contradicted by mark-specific loss/restoration and acute RNA effects (PMID38724747,36859550)."
      }
    ],
    "tournament_summary": "Descriptive comparison; does not modify the nominal score. Policarpi endogenous MLL2 catalytic knock-in/restoration distinguishes functional marks from a universally downstream signature. Its paired-mark arm uses engineered reporters, leaving feedback versus strict combinatorial instruction to the registered factorial native-locus experiment.",
    "study_separating_rank1_from_rank2": "Policarpi endogenous MLL2 catalytic knock-in/restoration distinguishes functional marks from a universally downstream signature. Its paired-mark arm uses engineered reporters, leaving feedback versus strict combinatorial instruction to the registered factorial native-locus experiment.",
    "nominal_wins_only_by_funding_artifact": false,
    "level_unchanged_by_tournament": true
  },
  "evidence_inventory": [
    {
      "n": 1,
      "pmid": "28967912",
      "title": "Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability.",
      "citation": "Rickels R, Herz HM, Sze CC et al. Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nature genetics. 2017.",
      "doi": "10.1038/ng.3965",
      "pmcid": "PMC5663216",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28967912/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28967912/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID28967912",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods & Materials, 2:Main text. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "fly and mouse stem-cell genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Catalytic-deficient Trr rescues fly viability; enhancer methylation changes have small transcriptional effects with stress-dependent exceptions.",
      "what_it_does_not_show": "Does not make all marks dispensable; genomic transgene rescue, residual marks, stress phenotypes and mammalian lineage limits matter.",
      "confounders_present": [
        "Does not make all marks dispensable; genomic transgene rescue, residual marks, stress phenotypes and mammalian lineage limits matter."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
      },
      "shared_components": [
        "Mouse enhancer comparison integrates Dorighi PMID28483418 data; independent fly rescue arm."
      ]
    },
    {
      "n": 2,
      "pmid": "37386214",
      "title": "Readout of histone methylation by Trim24 locally restricts chromatin opening by p53.",
      "citation": "Isbel L, Iskar M, Durdu S et al. Readout of histone methylation by Trim24 locally restricts chromatin opening by p53. Nature structural & molecular biology. 2023.",
      "doi": "10.1038/s41594-023-01021-8",
      "pmcid": "PMC10352137",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37386214/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37386214/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID37386214",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "cellular p53/Trim24 perturbation",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Trim24 couples unmethylated H3K4 recognition to local restriction of p53 chromatin opening and gene activation.",
      "what_it_does_not_show": "A cofactor-context mechanism is not a factorial demonstration of a multi-mark instruction code.",
      "confounders_present": [
        "A cofactor-context mechanism is not a factorial demonstration of a multi-mark instruction code."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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      },
      "shared_components": []
    },
    {
      "n": 3,
      "pmid": "33526675",
      "title": "Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.",
      "citation": "Zhao S, Chuh KN, Zhang B et al. Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proceedings of the National Academy of Sciences of the United States of America. 2021.",
      "doi": "10.1073/pnas.2016742118",
      "pmcid": "PMC8017887",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33526675/",
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      "tier": "A",
      "source_tier": "A",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID33526675",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "biochemical reader/writer/eraser assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3Q5ser enhances TAF3 readout and inhibits selected H3K4 erasers without equally changing all readers or writers.",
      "what_it_does_not_show": "Binding and turnover effects do not establish endogenous combination-specific transcription beyond individual marks.",
      "confounders_present": [
        "Binding and turnover effects do not establish endogenous combination-specific transcription beyond individual marks."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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        "supporting_count": 0,
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      },
      "shared_components": [
        "Related serotonylation programme with PMID30867594; mechanistic extension, not independent full causal replication."
      ]
    },
    {
      "n": 4,
      "pmid": "18682226",
      "title": "Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3.",
      "citation": "van Ingen H, van Schaik FM, Wienk H et al. Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure (London, England : 1993). 2008.",
      "doi": "10.1016/j.str.2008.04.015",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18682226/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18682226/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID18682226",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "NMR and peptide mutagenesis",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "TAF3 PHD structure explains H3K4me3 recognition and antagonism by H3R2 methylation.",
      "what_it_does_not_show": "A proposed methyl-methyl switch remains biochemical without locus-specific functional testing here.",
      "confounders_present": [
        "A proposed methyl-methyl switch remains biochemical without locus-specific functional testing here."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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        "supporting_count": 0,
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      },
      "shared_components": []
    },
    {
      "n": 5,
      "pmid": "42165139",
      "title": "Combinatorial histone modifications direct ATP-dependent chromatin remodeling by NURF to promoter-proximal nucleosomes.",
      "citation": "Kwon SY, Jang B, Grisan V et al. Combinatorial histone modifications direct ATP-dependent chromatin remodeling by NURF to promoter-proximal nucleosomes. Nucleic acids research. 2026.",
      "doi": "10.1093/nar/gkag494",
      "pmcid": "PMC13191287",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42165139/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42165139/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID42165139",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph4, 2:Results:paragraph8, 2:Results:paragraph13, 2:Results:paragraph16, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph22, 2:Results:paragraph24, 2:Results:paragraph26, 2:Results:paragraph27. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "Drosophila genetics, ChIP, FRAP and CAGE",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "NURF recognizes triply modified H3; writer deletions/reader-domain truncation impair stable recruitment; whole Nurf301 mutants alter nucleosome positions and transcript output.",
      "what_it_does_not_show": "Recruitment and whole-complex loss are distinct tests; high-mark housekeeping promoters increase expression after NURF loss. No endogenous factorial single/pair/triple transcription rescue isolates emergent code output.",
      "confounders_present": [
        "Recruitment and whole-complex loss are distinct tests; high-mark housekeeping promoters increase expression after NURF loss. No endogenous factorial single/pair/triple transcription rescue isolates emergent code output."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 6,
      "pmid": "21596426",
      "title": "Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.",
      "citation": "Ruthenburg AJ, Li H, Milne TA et al. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell. 2011.",
      "doi": "10.1016/j.cell.2011.03.053",
      "pmcid": "PMC3135172",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21596426/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21596426/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID21596426",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:RESULTS:paragraph1, 0:RESULTS:paragraph2, 0:RESULTS:paragraph4, 0:RESULTS:paragraph6, 0:RESULTS:paragraph10, 0:RESULTS:paragraph12, 0:RESULTS:paragraph13, 0:RESULTS:paragraph14. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "semisynthetic nucleosomes and cellular ChIP",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "BPTF distinguishes H3K4me3/H4K16ac at nucleosome level and binding-pocket/linker mutants impair tagged BPTF localization.",
      "what_it_does_not_show": "No endogenous transcriptional necessity test; ectopic tagged BPTF coexists with native protein and free-peptide binding lacks detectable allostery.",
      "confounders_present": [
        "No endogenous transcriptional necessity test; ectopic tagged BPTF coexists with native protein and free-peptide binding lacks detectable allostery."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 7,
      "pmid": "40637225",
      "title": "Molecular determinants for recognition of serotonylated chromatin.",
      "citation": "Pulido-Cortés L, Gielingh H, Thijssen V et al. Molecular determinants for recognition of serotonylated chromatin. Nucleic acids research. 2025.",
      "doi": "10.1093/nar/gkaf612",
      "pmcid": "PMC12238850",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40637225/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40637225/",
      "tier": "A",
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      "opened": true,
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      "what_it_shows": "TAF3 PHD has a defined surface recognizing H3Q5ser alongside H3K4me3.",
      "what_it_does_not_show": "Structural specificity does not demonstrate endogenous combinatorial transcriptional dependence.",
      "confounders_present": [
        "Structural specificity does not demonstrate endogenous combinatorial transcriptional dependence."
      ],
      "verification": "verified",
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      "pmid": "38513661",
      "title": "H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation.",
      "citation": "Kubo N, Chen PB, Hu R et al. H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation. Molecular cell. 2024.",
      "doi": "10.1016/j.molcel.2024.02.030",
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        "SC2",
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      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse ESC neural differentiation genetics",
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      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "KMT2C/D catalytic activity supports H3K4me1 and promoter-enhancer contacts at a subset of induced enhancers; KMT2B depletion worsens defects at retained sites.",
      "what_it_does_not_show": "Contacts are not alone causal transcription; redundant writers and enhancer subclasses limit a universal activation rule.",
      "confounders_present": [
        "Contacts are not alone causal transcription; redundant writers and enhancer subclasses limit a universal activation rule."
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    {
      "n": 9,
      "pmid": "33712604",
      "title": "Interplay of BAF and MLL4 promotes cell type-specific enhancer activation.",
      "citation": "Park YK, Lee JE, Yan Z et al. Interplay of BAF and MLL4 promotes cell type-specific enhancer activation. Nature communications. 2021.",
      "doi": "10.1038/s41467-021-21893-y",
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      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "adipogenic cellular depletion",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "BAF and MLL4 reciprocally support recruitment and lineage-factor-dependent enhancer activation; PBAF provides a context contrast.",
      "what_it_does_not_show": "Protein depletion does not separate catalytic marks from coactivator scaffolds or establish combination synergy.",
      "confounders_present": [
        "Protein depletion does not separate catalytic marks from coactivator scaffolds or establish combination synergy."
      ],
      "verification": "verified",
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    {
      "n": 10,
      "pmid": "27698142",
      "title": "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition.",
      "citation": "Wang C, Lee JE, Lai B et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proceedings of the National Academy of Sciences of the United States of America. 2016.",
      "doi": "10.1073/pnas.1606857113",
      "pmcid": "PMC5081576",
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      "access_depth": "abstract_metadata",
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        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "ESC differentiation and reprogramming genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "MLL4 supports cell fate transition and p300 recruitment while maintenance/self-renewal can persist without it.",
      "what_it_does_not_show": "The protein rather than its methylation activity controls p300 recruitment; no strict two-mark code follows.",
      "confounders_present": [
        "The protein rather than its methylation activity controls p300 recruitment; no strict two-mark code follows."
      ],
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    {
      "n": 11,
      "pmid": "26802126",
      "title": "Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain.",
      "citation": "Tie F, Banerjee R, Fu C et al. Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain. Proceedings of the National Academy of Sciences of the United States of America. 2016.",
      "doi": "10.1073/pnas.1515465113",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/26802126/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "fly genetics and biochemical CBP assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Polycomb directly binds and inhibits CBP, linking histone acetylation to protein interaction regulation.",
      "what_it_does_not_show": "CBP autoacetylation, protein contacts and overexpression confound attribution to a histone combination alone.",
      "confounders_present": [
        "CBP autoacetylation, protein contacts and overexpression confound attribution to a histone combination alone."
      ],
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    {
      "n": 12,
      "pmid": "37012455",
      "title": "MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner.",
      "citation": "Xie G, Lee JE, Senft AD et al. MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner. Nature genetics. 2023.",
      "doi": "10.1038/s41588-023-01356-4",
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        "SC2",
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      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse lineage-restricted catalytic genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Eliminating MLL3/4 catalysis impairs extraembryonic lineages and gastrulation while embryonic-lineage differentiation is less dependent.",
      "what_it_does_not_show": "Contradicts unlimited dispensability and unlimited necessity alike; lineage function does not isolate a combinatorial reader code.",
      "confounders_present": [
        "Contradicts unlimited dispensability and unlimited necessity alike; lineage function does not isolate a combinatorial reader code."
      ],
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    {
      "n": 13,
      "pmid": "29404406",
      "title": "An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells.",
      "citation": "Cao K, Collings CK, Morgan MA et al. An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells. Science advances. 2018.",
      "doi": "10.1126/sciadv.aap8747",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/29404406/",
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      "relates_to_subclaims": [
        "SC2",
        "SC3"
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      "evidence_class": "Strong",
      "system": "ESC null/catalytic genetics with LSD1 contrast",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Mll4 is needed to exit naive pluripotency but its catalytic activity is dispensable; LSD1 depletion rescues Mll4-null transition.",
      "what_it_does_not_show": "Co-regulator compensation supports a regulatory axis rather than proof that marks never act causally.",
      "confounders_present": [
        "Co-regulator compensation supports a regulatory axis rather than proof that marks never act causally."
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      "title": "A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.",
      "citation": "Hoshii T, Cifani P, Feng Z et al. A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell. 2018.",
      "doi": "10.1016/j.cell.2018.01.032",
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      "evidence_class": "Strong",
      "system": "AML CRISPR domain screening",
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      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "SETD1A FLOS/cyclin-K function controls survival and DNA damage response despite dispensable SET catalytic domain.",
      "what_it_does_not_show": "A noncatalytic dependency cannot be counted as evidence for histone methylation or mark-combination causality.",
      "confounders_present": [
        "A noncatalytic dependency cannot be counted as evidence for histone methylation or mark-combination causality."
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      "pmid": "26472914",
      "title": "Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.",
      "citation": "Jiao L, Liu X et al. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science (New York, N.Y.). 2015.",
      "doi": "10.1126/science.aac4383",
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        "SC3"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "purified PRC2 crystallography",
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      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "EED/EZH2 structures explain allosteric stimulation by H3K27me3 and catalytic organization.",
      "what_it_does_not_show": "Cell-free structural feedback is capped for endogenous causal output.",
      "confounders_present": [
        "Cell-free structural feedback is capped for endogenous causal output."
      ],
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      "pmid": "24289921",
      "title": "Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity.",
      "citation": "Ferrari KJ, Scelfo A, Jammula S et al. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Molecular cell. 2014.",
      "doi": "10.1016/j.molcel.2013.10.030",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/24289921/",
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      "relates_to_subclaims": [
        "SC2",
        "SC3"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "mouse ESC PRC2 genetic analysis",
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      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Different H3K27 methylation states associate with distinct genomic functions and perturbations affect transcription/enhancer fidelity.",
      "what_it_does_not_show": "Complex loss and secondary H3K36 interactions make individual-state specificity and combinatorial effects difficult to isolate.",
      "confounders_present": [
        "Complex loss and secondary H3K36 interactions make individual-state specificity and combinatorial effects difficult to isolate."
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      "n": 17,
      "pmid": "21549310",
      "title": "Histone methylation by PRC2 is inhibited by active chromatin marks.",
      "citation": "Schmitges FW, Prusty AB, Faty M et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Molecular cell. 2011.",
      "doi": "10.1016/j.molcel.2011.03.025",
      "pmcid": "",
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "cross-species PRC2 reconstitution",
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      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me3/H3K36 methylation inhibit PRC2 while H3K27me3 stimulates it.",
      "what_it_does_not_show": "Biochemical writer crosstalk establishes plausibility, not transcriptional instruction at endogenous loci.",
      "confounders_present": [
        "Biochemical writer crosstalk establishes plausibility, not transcriptional instruction at endogenous loci."
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      "pmid": "25849900",
      "title": "Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers.",
      "citation": "Hilton IB, D'Ippolito AM, Vockley CM et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nature biotechnology. 2015.",
      "doi": "10.1038/nbt.3199",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/25849900/",
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      "relates_to_subclaims": [
        "SC2",
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "targeted dCas9-p300 cellular editing",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Recruiting p300 catalytic core to selected promoters/enhancers activates target genes with localized H3K27ac.",
      "what_it_does_not_show": "Ectopic recruitment and multiple p300 substrates do not isolate one residue or an endogenous combination-specific mechanism.",
      "confounders_present": [
        "Ectopic recruitment and multiple p300 substrates do not isolate one residue or an endogenous combination-specific mechanism."
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      "n": 19,
      "pmid": "33231641",
      "title": "Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation.",
      "citation": "Ryu HY, Zhao D, Li J et al. Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation. Nucleic acids research. 2020.",
      "doi": "10.1093/nar/gkaa1093",
      "pmcid": "PMC7708062",
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      "relates_to_subclaims": [
        "SC2",
        "SC3"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "yeast histone/Set3 genetic pathway",
      "decisive_perturbation": false,
      "endogenous": false,
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      "what_it_shows": "Sumoylation recruits Set3 HDAC through Cpr1 and cooperates with H2Bub/H3K4me2 to suppress cryptic transcription.",
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      "title": "Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation.",
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      "what_it_does_not_show": "Purified writer activity is not endogenous transcriptional causality.",
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      "title": "Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L Methyltransferase.",
      "citation": "Anderson CJ, Baird MR, Hsu A et al. Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L Methyltransferase. Cell reports. 2019.",
      "doi": "10.1016/j.celrep.2019.01.058",
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      "what_it_shows": "Dot1L contacts ubiquitin and the acidic patch in a methylation-ready configuration.",
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        "Structural activation does not establish a combinatorial gene-output code."
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      "title": "Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate.",
      "citation": "Fuchs G, Hollander D, Voichek Y et al. Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate. Genome research. 2014.",
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      "system": "live-cell transcription/ChIP time course",
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      "what_it_shows": "H2Bub tracks polymerase advance and elongation rate more closely than slower methyl marks.",
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        "A cotranscriptional readout is not an upstream instruction; pausing associations do not establish primacy."
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      "n": 23,
      "pmid": "31922488",
      "title": "Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome.",
      "citation": "Worden EJ, Zhang X, Wolberger C et al. Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome. eLife. 2020.",
      "doi": "10.7554/eLife.53199",
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      "what_it_shows": "COMPASS bridges ubiquitin and nucleosome contacts to stimulate H3K4 methylation across histone tails.",
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        "Reconstituted crosstalk does not specify endogenous transcriptional output beyond constituent effects."
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      "title": "Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation.",
      "citation": "Valencia-Sánchez MI, De Ioannes P, Wang M et al. Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation. Science (New York, N.Y.). 2021.",
      "doi": "10.1126/science.abc6663",
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        "Writer stimulation and epigenetic maintenance are not a general deterministic code; full report access remains abstract-only here."
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      "title": "Nucleosome contact triggers conformational changes of Rpd3S driving high-affinity H3K36me nucleosome engagement.",
      "citation": "Ruan C, Lee CH, Cui H et al. Nucleosome contact triggers conformational changes of Rpd3S driving high-affinity H3K36me nucleosome engagement. Cell reports. 2015.",
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      "what_it_does_not_show": "Multivalent chromatin engagement includes unmodified structural contacts; not necessarily a specific mark-combination instruction.",
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        "Multivalent chromatin engagement includes unmodified structural contacts; not necessarily a specific mark-combination instruction."
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      "n": 26,
      "pmid": "26602082",
      "title": "Global mapping of the regulatory interactions of histone residues.",
      "citation": "Jung I, Seo J, Lee HS et al. Global mapping of the regulatory interactions of histone residues. FEBS letters. 2015.",
      "doi": "10.1016/j.febslet.2015.11.016",
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      "system": "yeast histone point-mutant expression mapping",
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      "what_it_shows": "Histone-residue perturbations map regulatory associations with methylases and deacetylases.",
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        "Mutations alter residue chemistry and expression similarity does not by itself establish epistasis or specific combinatorial reading."
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      "pmid": "32521276",
      "title": "Unique and Shared Roles for Histone H3K36 Methylation States in Transcription Regulation Functions.",
      "citation": "DiFiore JV, Ptacek TS, Wang Y et al. Unique and Shared Roles for Histone H3K36 Methylation States in Transcription Regulation Functions. Cell reports. 2020.",
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      "what_it_shows": "Engineered methylation states show shared cryptic-transcription suppression and a distinct H3K36me3-associated Bur1/FACT function.",
      "what_it_does_not_show": "Redundancy among states limits a one-state/one-output vocabulary; stress and yeast scope remain bounded.",
      "confounders_present": [
        "Redundancy among states limits a one-state/one-output vocabulary; stress and yeast scope remain bounded."
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      "pmid": "31543422",
      "title": "Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism.",
      "citation": "Wang L, Gao Y, Zheng X et al. Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism. Molecular cell. 2019.",
      "doi": "10.1016/j.molcel.2019.08.019",
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        "In vitro droplets and exclusion do not establish endogenous phase separation or transcriptional instruction."
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      "title": "Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B.",
      "citation": "Rondelet G, Dal Maso T, Willems L et al. Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. Journal of structural biology. 2016.",
      "doi": "10.1016/j.jsb.2016.03.013",
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      "what_it_shows": "DNMT3B recognizes H3K36me3 through a defined aromatic/water pocket; a disease mutation disrupts affinity.",
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      "pmid": "37945563",
      "title": "Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation.",
      "citation": "Harris RJ, Heer M, Levasseur MD et al. Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation. Nature communications. 2023.",
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    {
      "n": 31,
      "pmid": "16630819",
      "title": "A bivalent chromatin structure marks key developmental genes in embryonic stem cells.",
      "citation": "Bernstein BE, Mikkelsen TS, Xie X et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006.",
      "doi": "10.1016/j.cell.2006.02.041",
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      "what_it_shows": "Developmental promoters carry regional H3K4/H3K27 bivalency and low expression with sequence associations.",
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    {
      "n": 32,
      "pmid": "23021224",
      "title": "Asymmetrically modified nucleosomes.",
      "citation": "Voigt P, LeRoy G, Drury WJ et al. Asymmetrically modified nucleosomes. Cell. 2012.",
      "doi": "10.1016/j.cell.2012.09.002",
      "pmcid": "PMC3498816",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23021224/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "native nucleosome profiling and PRC2 assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Bivalent marks occupy opposite H3 tails; asymmetric placement permits PRC2 activity unlike symmetric placement.",
      "what_it_does_not_show": "Nucleosomal asymmetry changes biochemistry; functional poising requires separate perturbation evidence.",
      "confounders_present": [
        "Nucleosomal asymmetry changes biochemistry; functional poising requires separate perturbation evidence."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 33,
      "pmid": "39731917",
      "title": "Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains.",
      "citation": "Bryan E, Valsakumar D, Idigo NJ et al. Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains. Molecular cell. 2025.",
      "doi": "10.1016/j.molcel.2024.12.002",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39731917/",
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      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "ESC bivalent proteomics and KAT6B knockout",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Asymmetric bivalent nucleosomes recruit KAT6B beyond either mark alone; KAT6B loss blocks neuronal differentiation.",
      "what_it_does_not_show": "Reader-complex loss is not factorial mark removal with rescue; developmental failure need not prove the combination itself specifies output.",
      "confounders_present": [
        "Reader-complex loss is not factorial mark removal with rescue; developmental failure need not prove the combination itself specifies output."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 34,
      "pmid": "27151869",
      "title": "Single-molecule decoding of combinatorially modified nucleosomes.",
      "citation": "Shema E, Jones D, Shoresh N et al. Single-molecule decoding of combinatorially modified nucleosomes. Science (New York, N.Y.). 2016.",
      "doi": "10.1126/science.aad7701",
      "pmcid": "PMC4904710",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27151869/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "single-molecule nucleosome imaging",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Directly detects co-modified nucleosomes and state-specific effects of enzyme perturbation.",
      "what_it_does_not_show": "Technology and state abundance do not establish causal combinations beyond additive effects.",
      "confounders_present": [
        "Technology and state abundance do not establish causal combinations beyond additive effects."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 35,
      "pmid": "21164480",
      "title": "TRIM24 links a non-canonical histone signature to breast cancer.",
      "citation": "Tsai WW, Wang Z, Yiu TT et al. TRIM24 links a non-canonical histone signature to breast cancer. Nature. 2010.",
      "doi": "10.1038/nature09542",
      "pmcid": "PMC3058826",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21164480/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21164480/",
      "tier": "A",
      "source_tier": "A",
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      ],
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      "status_checked_on": "2026-10-09",
      "study_id": "PMID21164480",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "TRIM24 structural/cellular perturbation",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "TRIM24 tandem reader recognizes H3K4me0/H3K23ac and supports estrogen-dependent gene activation.",
      "what_it_does_not_show": "Patient survival is associative; reader/protein effects do not independently manipulate both endogenous marks.",
      "confounders_present": [
        "Patient survival is associative; reader/protein effects do not independently manipulate both endogenous marks."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 36,
      "pmid": "31564646",
      "title": "H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling.",
      "citation": "Luo M, Bai J, Liu B et al. H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling. Stem cell reports. 2019.",
      "doi": "10.1016/j.stemcr.2019.08.016",
      "pmcid": "PMC6830056",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31564646/",
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      "study_id": "PMID31564646",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "ESC versus embryoid-body TRIM33 perturbation",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K18ac and TRIM33 accessibility prime nodal responses in embryoid bodies with a contrasting ESC context.",
      "what_it_does_not_show": "p300/HDAC1 regulate multiple substrates; the specific two-mark interaction is not independently factorially tested.",
      "confounders_present": [
        "p300/HDAC1 regulate multiple substrates; the specific two-mark interaction is not independently factorially tested."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 37,
      "pmid": "22196728",
      "title": "A poised chromatin platform for TGF-β access to master regulators.",
      "citation": "Xi Q, Wang Z, Zaromytidou AI et al. A poised chromatin platform for TGF-β access to master regulators. Cell. 2011.",
      "doi": "10.1016/j.cell.2011.11.032",
      "pmcid": "PMC3582033",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22196728/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22196728/",
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      "study_id": "PMID22196728",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph13, 1:Results:paragraph15, 1:Results:paragraph16, 1:Results:paragraph17, 1:Results:paragraph18, 1:Results:paragraph20. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse/human ESC TRIM33 loss and rescue",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
      "what_it_does_not_show": "Positive threshold crossing is for reader-dependent contextual gene activation, not proof of supra-additive endogenous mark combinations. PHD deletion and writer feedback remain alternatives.",
      "confounders_present": [
        "Positive threshold crossing is for reader-dependent contextual gene activation, not proof of supra-additive endogenous mark combinations. PHD deletion and writer feedback remain alternatives."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 38,
      "pmid": "24039962",
      "title": "Multivalent engagement of TFIID to nucleosomes.",
      "citation": "van Nuland R, Schram AW, van Schaik FM et al. Multivalent engagement of TFIID to nucleosomes. PloS one. 2013.",
      "doi": "10.1371/journal.pone.0073495",
      "pmcid": "PMC3770614",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24039962/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24039962/",
      "tier": "A",
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      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID24039962",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "TFIID reconstitution and cellular TAF3 assay",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me3, acetylation and TATA DNA synergize in TFIID binding, and TAF3 PHD supports rapid gene induction.",
      "what_it_does_not_show": "Binding synergy with DNA is not factorial endogenous histone-only output dependence.",
      "confounders_present": [
        "Binding synergy with DNA is not factorial endogenous histone-only output dependence."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 39,
      "pmid": "17884155",
      "title": "Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4.",
      "citation": "Vermeulen M, Mulder KW, Denissov S et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell. 2007.",
      "doi": "10.1016/j.cell.2007.08.016",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/17884155/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17884155/",
      "tier": "A",
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      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID17884155",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "TFIID proteomics and cellular mark depletion",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me3 loss reduces TFIID/promoter activity in subsets; R2 methylation antagonizes and acetylation potentiates binding.",
      "what_it_does_not_show": "Selective single-mark effects and transient coactivation do not establish a general multi-mark code.",
      "confounders_present": [
        "Selective single-mark effects and transient coactivation do not establish a general multi-mark code."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 40,
      "pmid": "23452851",
      "title": "H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation.",
      "citation": "Lauberth SM, Nakayama T, Wu X et al. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell. 2013.",
      "doi": "10.1016/j.cell.2013.01.052",
      "pmcid": "PMC3588593",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23452851/",
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      "tier": "A",
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        "none_found"
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      "opened": true,
      "opened_on": "2026-10-09",
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      "study_id": "PMID23452851",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "TAF3/p53 transcriptional perturbation",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me3-TAF3 supports PIC assembly and selective p53 activation, cooperatively with TATA elements.",
      "what_it_does_not_show": "DNA/mark cooperation and cellular context do not demonstrate histone-combination causality.",
      "confounders_present": [
        "DNA/mark cooperation and cellular context do not demonstrate histone-combination causality."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 41,
      "pmid": "16222246",
      "title": "Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation.",
      "citation": "Fischle W, Tseng BS, Dormann HL et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature. 2005.",
      "doi": "10.1038/nature04219",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16222246/",
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID16222246",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "Aurora-B perturbation and HP1 localization",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3S10 phosphorylation ejects HP1 despite persistent H3K9me3; Aurora-B inhibition retains HP1 in mitosis.",
      "what_it_does_not_show": "HP1 relocation is a protein/chromatin endpoint, not direct combination-specific transcriptional output.",
      "confounders_present": [
        "HP1 relocation is a protein/chromatin endpoint, not direct combination-specific transcriptional output."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 42,
      "pmid": "16222244",
      "title": "Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin.",
      "citation": "Hirota T, Lipp JJ, Toh BH et al. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature. 2005.",
      "doi": "10.1038/nature04254",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16222244/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16222244/",
      "tier": "A",
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      ],
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      "opened_on": "2026-10-09",
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      "study_id": "PMID16222244",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "mitotic kinase perturbation and chromatin assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K9me3S10ph marks mitotic heterochromatin and blocked phosphorylation prevents HP1 release.",
      "what_it_does_not_show": "Supports a reader-binding switch but not the registered transcription code; mitotic kinase pleiotropy needs controls.",
      "confounders_present": [
        "Supports a reader-binding switch but not the registered transcription code; mitotic kinase pleiotropy needs controls."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 43,
      "pmid": "15795371",
      "title": "Genomic characterization reveals a simple histone H4 acetylation code.",
      "citation": "Dion MF, Altschuler SJ, Wu LF et al. Genomic characterization reveals a simple histone H4 acetylation code. Proceedings of the National Academy of Sciences of the United States of America. 2005.",
      "doi": "10.1073/pnas.0500136102",
      "pmcid": "PMC555684",
      "url": "https://pubmed.ncbi.nlm.nih.gov/15795371/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15795371/",
      "tier": "A",
      "source_tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID15795371",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "factorial yeast H4 lysine-substitution genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "All H4 lysine-mutant combinations separate a specific K16 effect from cumulative K5/K8/K12 transcription effects.",
      "what_it_does_not_show": "Arginine substitutes charge/nonmodifiable chemistry, not acetylation alone; findings are yeast H4 scope rather than universal refutation.",
      "confounders_present": [
        "Arginine substitutes charge/nonmodifiable chemistry, not acetylation alone; findings are yeast H4 scope rather than universal refutation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 44,
      "pmid": "28483418",
      "title": "Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation.",
      "citation": "Dorighi KM, Swigut T, Henriques T et al. Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation. Molecular cell. 2017.",
      "doi": "10.1016/j.molcel.2017.04.018",
      "pmcid": "PMC5662137",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28483418/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph13. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse ESC catalytic-point-mutant versus deletion",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Stable catalytic-null Mll3/4 proteins retain enhancer transcription despite mark loss; protein deletion suppresses polymerase/eRNA and nearby genes.",
      "what_it_does_not_show": "Residual H3K4me1 and naive ESC state constrain dispensability; protein dependence is not mark dependence.",
      "confounders_present": [
        "Residual H3K4me1 and naive ESC state constrain dispensability; protein dependence is not mark dependence."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      },
      "shared_components": [
        "Mouse enhancer data reused for comparison in Rickels PMID28967912."
      ]
    },
    {
      "n": 45,
      "pmid": "29313530",
      "title": "Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers.",
      "citation": "Yan J, Chen SA, Local A et al. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell research. 2018.",
      "doi": "10.1038/cr.2018.1",
      "pmcid": "PMC5799818",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29313530/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29313530/",
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      "status_flags": [
        "ErratumIn: PMID29497152"
      ],
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      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID29313530",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "differentiating ESC genetics and contact assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "MLL3/4-dependent H3K4me1 contributes to cohesin recruitment, contacts and differentiation-linked gene activation.",
      "what_it_does_not_show": "Mark/protein perturbation and contacts need specificity; linked erratum attached and its detailed correction was not independently examined.",
      "confounders_present": [
        "Mark/protein perturbation and contacts need specificity; linked erratum attached and its detailed correction was not independently examined."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "shared_components": []
    },
    {
      "n": 46,
      "pmid": "32085783",
      "title": "Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells.",
      "citation": "Zhang T, Zhang Z, Dong Q et al. Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells. Genome biology. 2020.",
      "doi": "10.1186/s13059-020-01957-w",
      "pmcid": "PMC7035716",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32085783/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32085783/",
      "tier": "A",
      "source_tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID32085783",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results and discussion:paragraph0, 1:Results and discussion:paragraph2, 1:Results and discussion:paragraph3, 1:Results and discussion:paragraph4, 1:Results and discussion:paragraph6, 1:Results and discussion:paragraph7, 1:Results and discussion:paragraph8. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "endogenous H3.3K27R mouse ESC genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Mutating both H3.3 genes sharply reduces enhancer H3K27ac while many transcripts/accessibility features persist.",
      "what_it_does_not_show": "Canonical H3 remains modifiable and other acetyl marks remain; no total-H3K27ac or all-context dispensability follows.",
      "confounders_present": [
        "Canonical H3 remains modifiable and other acetyl marks remain; no total-H3K27ac or all-context dispensability follows."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 47,
      "pmid": "36869380",
      "title": "Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during embryonic stem cell differentiation.",
      "citation": "Boileau RM, Chen KX, Blelloch R et al. Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during embryonic stem cell differentiation. Genome biology. 2023.",
      "doi": "10.1186/s13059-023-02883-3",
      "pmcid": "PMC9983171",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36869380/",
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      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID36869380",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "ESC differentiation MLL3/4 loss",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Many enhancers lose changing H3K4me1/H3K27ac without preventing activation of nearby genes; stable and dynamic sites differ.",
      "what_it_does_not_show": "Nearest-gene assignment and alternative activating pathways constrain inference; this is not proof all enhancer marks are inert.",
      "confounders_present": [
        "Nearest-gene assignment and alternative activating pathways constrain inference; this is not proof all enhancer marks are inert."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 48,
      "pmid": "16364921",
      "title": "Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation.",
      "citation": "Joshi AA, Struhl K et al. Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Molecular cell. 2005.",
      "doi": "10.1016/j.molcel.2005.11.021",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16364921/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16364921/",
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID16364921",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "yeast Eaf3/Set2 genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Eaf3 recognition of methylated H3K36 supports coding-region deacetylation and suppresses internal initiation.",
      "what_it_does_not_show": "A transcription-coupled reader pathway is not necessarily simultaneous combinatorial instruction.",
      "confounders_present": [
        "A transcription-coupled reader pathway is not necessarily simultaneous combinatorial instruction."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      "shared_components": []
    },
    {
      "n": 49,
      "pmid": "16286007",
      "title": "Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription.",
      "citation": "Carrozza MJ, Li B, Florens L et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005.",
      "doi": "10.1016/j.cell.2005.10.023",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16286007/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16286007/",
      "tier": "A",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID16286007",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "yeast Set2/Rpd3S mutant transcription",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
      "what_it_does_not_show": "Establishes a causal mark/reader pathway at coding regions, not a rich deterministic multi-mark code.",
      "confounders_present": [
        "Establishes a causal mark/reader pathway at coding regions, not a rich deterministic multi-mark code."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      },
      "shared_components": []
    },
    {
      "n": 50,
      "pmid": "16286008",
      "title": "Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex.",
      "citation": "Keogh MC, Kurdistani SK, Morris SA et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell. 2005.",
      "doi": "10.1016/j.cell.2005.10.025",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16286008/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16286008/",
      "tier": "A",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID16286008",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "independent yeast Set2/Rpd3 complex genetics",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
      "what_it_does_not_show": "Shares yeast pathway biology with other reports; distinct laboratory work is not proof of universal combinatorial encoding.",
      "confounders_present": [
        "Shares yeast pathway biology with other reports; distinct laboratory work is not proof of universal combinatorial encoding."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      },
      "shared_components": []
    },
    {
      "n": 51,
      "pmid": "12077605",
      "title": "Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.",
      "citation": "Sun ZW, Allis CD et al. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002.",
      "doi": "10.1038/nature00883",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12077605/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12077605/",
      "tier": "A",
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      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID12077605",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "yeast histone K123/K4 mutant epistasis",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
      "what_it_does_not_show": "Residue mutations and Rad6 pleiotropy constrain specificity; ordered writer crosstalk is distinct from emergent output encoding.",
      "confounders_present": [
        "Residue mutations and Rad6 pleiotropy constrain specificity; ordered writer crosstalk is distinct from emergent output encoding."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "shared_components": []
    },
    {
      "n": 52,
      "pmid": "14660634",
      "title": "Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription.",
      "citation": "Daniel JA, Torok MS, Sun ZW et al. Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. The Journal of biological chemistry. 2004.",
      "doi": "10.1074/jbc.C300494200",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/14660634/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/14660634/",
      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID14660634",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "yeast Ubp8/SAGA genetic perturbation",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Regulated H2B deubiquitination supports GAL10 activation and coupled H3K4 methylation.",
      "what_it_does_not_show": "SAGA also acetylates and scaffolds transcription; multiple functions prevent code-only attribution.",
      "confounders_present": [
        "SAGA also acetylates and scaffolds transcription; multiple functions prevent code-only attribution."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      "shared_components": []
    },
    {
      "n": 53,
      "pmid": "19767730",
      "title": "Role of the polycomb protein EED in the propagation of repressive histone marks.",
      "citation": "Margueron R, Justin N, Ohno K et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 2009.",
      "doi": "10.1038/nature08398",
      "pmcid": "PMC3772642",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19767730/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19767730/",
      "tier": "A",
      "source_tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID19767730",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "EED structural biochemistry and fly genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "EED recognizes repressive methyl-lysines to stimulate PRC2; binding mutants impair methylation/development.",
      "what_it_does_not_show": "Feedback propagation does not alone specify combinatorial transcription outputs.",
      "confounders_present": [
        "Feedback propagation does not alone specify combinatorial transcription outputs."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 54,
      "pmid": "19087956",
      "title": "Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.",
      "citation": "Jin Y, Rodriguez AM, Wyrick JJ et al. Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae. Genetics. 2009.",
      "doi": "10.1534/genetics.108.098897",
      "pmcid": "PMC2644940",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19087956/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19087956/",
      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID19087956",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "yeast simultaneous histone-mutant genetics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Acetylated/methylated residue mutants show growth interaction but largely independent gene-expression effects and different Sir4 binding.",
      "what_it_does_not_show": "Interdependence is phenotype-specific; residue replacements do not selectively erase one chemical mark.",
      "confounders_present": [
        "Interdependence is phenotype-specific; residue replacements do not selectively erase one chemical mark."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 55,
      "pmid": "12498683",
      "title": "Crosstalk between CARM1 methylation and CBP acetylation on histone H3.",
      "citation": "Daujat S, Bauer UM, Shah V et al. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Current biology : CB. 2002.",
      "doi": "10.1016/s0960-9822(02)01387-8",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12498683/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12498683/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID12498683",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "estrogen time course and CBP biochemistry",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Acetylation precedes CARM1 methylation and facilitates binding/activity at estrogen-responsive chromatin.",
      "what_it_does_not_show": "Exogenous CBP sufficiency and ordered deposition do not prove endogenous supra-additive combination output.",
      "confounders_present": [
        "Exogenous CBP sufficiency and ordered deposition do not prove endogenous supra-additive combination output."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 56,
      "pmid": "30867594",
      "title": "Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3.",
      "citation": "Farrelly LA, Thompson RE, Zhao S et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. 2019.",
      "doi": "10.1038/s41586-019-1024-7",
      "pmcid": "PMC6557285",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30867594/",
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      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID30867594",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "neuronal chromatin and ectopic H3 mutant",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me3Q5ser occurs in vivo, enhances TFIID interaction, and nonserotonylatable ectopic H3 alters differentiation/transcription.",
      "what_it_does_not_show": "Ectopic mutant and writer multiple substrates cap inference to endogenous combinatorial necessity.",
      "confounders_present": [
        "Ectopic mutant and writer multiple substrates cap inference to endogenous combinatorial necessity."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 57,
      "pmid": "16122352",
      "title": "Single-nucleosome mapping of histone modifications in S. cerevisiae.",
      "citation": "Liu CL, Kaplan T, Kim M et al. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS biology. 2005.",
      "doi": "10.1371/journal.pbio.0030328",
      "pmcid": "PMC1195719",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16122352/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16122352/",
      "tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID16122352",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "single-nucleosome yeast ChIP profiling",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "contradicts",
      "what_it_shows": "Twelve modifications form broad co-occurring gradients rather than many discrete deterministic states.",
      "what_it_does_not_show": "Observational mapping cannot disprove specific causal combinations elsewhere; continuous patterns may remain functional.",
      "confounders_present": [
        "Observational mapping cannot disprove specific causal combinations elsewhere; continuous patterns may remain functional."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 58,
      "pmid": "38724747",
      "title": "Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.",
      "citation": "Policarpi C, Munafò M, Tsagkris S et al. Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications. Nature genetics. 2024.",
      "doi": "10.1038/s41588-024-01706-w",
      "pmcid": "PMC11176084",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38724747/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38724747/",
      "tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID38724747",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph3, 1:Results:paragraph7, 1:Results:paragraph9, 1:Results:paragraph15, 1:Results:paragraph17, 1:Results:paragraph19, 1:Results:paragraph21, 1:Results:paragraph25, 1:Results:paragraph30, 1:Results:paragraph35, 1:Results:paragraph36. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "catalytic knock-in and controlled epigenome editing",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
      "what_it_does_not_show": "Paired-mark result is in engineered reporters, at least additive and potentially synergistic; it does not prove endogenous beyond-additive code necessity.",
      "confounders_present": [
        "Paired-mark result is in engineered reporters, at least additive and potentially synergistic; it does not prove endogenous beyond-additive code necessity."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 59,
      "pmid": "36859550",
      "title": "H3K4me3 regulates RNA polymerase II promoter-proximal pause-release.",
      "citation": "Wang H, Fan Z, Shliaha PV et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature. 2023.",
      "doi": "10.1038/s41586-023-05780-8",
      "pmcid": "PMC9995272",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36859550/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36859550/",
      "tier": "A",
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      "status_flags": [
        "ErratumIn: PMID36941349",
        "ErratumIn: PMID37907651"
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID36859550",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:H3K4me3 is required for transcription:paragraph0, 3:H3K4me3 is required for transcription:paragraph2, 4:Intact PIC formation after loss of H3K4me3. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "acute endogenous DPY30/RBBP5 degrons and KDM5 genetics",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists.",
      "what_it_does_not_show": "Shared SET1/COMPASS functions and proliferation effects limit perfect specificity; linked corrections remain attached, not separate primary counts.",
      "confounders_present": [
        "Shared SET1/COMPASS functions and proliferation effects limit perfect specificity; linked corrections remain attached, not separate primary counts."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 60,
      "pmid": "17997276",
      "title": "Combinatorial effects of four histone modifications in transcription and differentiation.",
      "citation": "Fischer JJ, Toedling J, Krueger T et al. Combinatorial effects of four histone modifications in transcription and differentiation. Genomics. 2008.",
      "doi": "10.1016/j.ygeno.2007.08.010",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/17997276/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17997276/",
      "tier": "A",
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        "none_found"
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID17997276",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "differentiation ChIP/expression profiling",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "Expression associations depend on mark combinations; many mark changes remain uncoupled from transcript changes.",
      "what_it_does_not_show": "This is observational combinatorial association rather than intervention-driven code validation.",
      "confounders_present": [
        "This is observational combinatorial association rather than intervention-driven code validation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 61,
      "pmid": "34309923",
      "title": "Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.",
      "citation": "Kang Y, Kim YW, Kang J et al. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021.",
      "doi": "10.1096/fj.202100488R",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34309923/",
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      "tier": "A",
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      "status_flags": [
        "none_found"
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID34309923",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "K562 catalytic-domain mutations and enhancer assays",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4me1/MLL3/4 and p300/H3K27ac perturbations affect eviction and eRNA asymmetrically at beta-globin enhancers.",
      "what_it_does_not_show": "Enzyme-domain lesions affect multiple outputs/substrates; differing individual roles do not establish supra-additivity.",
      "confounders_present": [
        "Enzyme-domain lesions affect multiple outputs/substrates; differing individual roles do not establish supra-additivity."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    {
      "n": 62,
      "pmid": "38417480",
      "title": "Histone H3K4ac, as a marker of active transcription start sites and enhancers, plays roles in histone eviction and RNA transcription.",
      "citation": "Kang J, Kang Y, Kim A et al. Histone H3K4ac, as a marker of active transcription start sites and enhancers, plays roles in histone eviction and RNA transcription. Biochimica et biophysica acta. Gene regulatory mechanisms. 2024.",
      "doi": "10.1016/j.bbagrm.2024.195021",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38417480/",
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      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
      "study_id": "PMID38417480",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "K562 acetylase/methylase-mutant chromatin",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "supports",
      "what_it_shows": "H3K4ac relates to eviction/transcription and can overlap redundantly with H3K27ac in eRNA regulation.",
      "what_it_does_not_show": "p300 and MLL3/4 affect many marks; interdependence and redundancy are distinct from a strict code.",
      "confounders_present": [
        "p300 and MLL3/4 affect many marks; interdependence and redundancy are distinct from a strict code."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      },
      "shared_components": []
    }
  ],
  "verification_summary": {
    "load_bearing_claims_checked": 66,
    "verified": 66,
    "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": "Genome-wide and single-nucleosome patterns reproducibly track transcription and developmental state (PMID16630819,27151869,17997276,16122352). This existence subclaim is supported by association, with continuous gradients and asymmetric nucleosomes limiting discrete-state interpretations; association alone is Β.",
      "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": "BPTF dual-mark recognition and binding mutants are real, but tagged localization is not transcriptional necessity (PMID21596426). TRIM33 loss/PHD rescue establishes contextual reader dependence, without independently factorially editing endogenous K9/K18 marks (PMID22196728). Paired Polycomb targeting increases reporter silencing with at least additive and potentially synergistic effects (PMID38724747); the combination arm remains reporter-based. NURF writer deletions/truncations test recruitment, whereas full Nurf301 deletion tests transcription, leaving the exact combination-to-output bridge unresolved (PMID42165139). KAT6B loss after bivalent-specific recruitment is also a protein-function test, not factorial mark necessity (PMID39731917). Therefore Δ for the registered emergent endogenous code is not yet crossed.",
      "resulting_ceiling": "Γ"
    }
  ],
  "cap_precedence_resolutions": [
    {
      "collision": "Perturbation in a defined setting versus broader inference",
      "subclaim_scope_cap_binds_on": "Specific combinations of histone modifications are read as a combinatorial code that causally specifies transcriptional outputs beyond the effects of individual marks.",
      "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope",
      "resolution": "Δ/Ζ for SC2 applies to specific endogenous mark/reader functions, supported by convergent classes. Γ for SC3 applies to inference from binding, reporter combinations and protein-domain/whole-complex perturbation to emergent endogenous mark-combination output. Targeted ectopic recruitment is not automatically dismissed: native single-mark loss plus restoration contributes to SC2, whereas native combination necessity is still absent. Positive narrow function, negative perturbation contrasts and presence are never pooled into a positive universal-code tally.",
      "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": [
        "Peptide/nucleosome affinity or crystallographic recognition alone is capped for endogenous transcriptional inference.",
        "Co-occurrence, FRAP and localization alone are not direct output dependence.",
        "Reporter-only paired-mark results and ectopic tagged or mutant histones cannot establish endogenous necessity; this does not cap the independent loss/restoration convergence for SC2.",
        "Protein/writer loss must be separated from deposited-mark effects, residual modifications, cell-cycle redistribution and global transcription/viability collapse."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Genome-wide and single-nucleosome patterns reproducibly track transcription and developmental state (PMID16630819,27151869,17997276,16122352). This existence subclaim is supported by association, with continuous gradients and asymmetric nucleosomes limiting discrete-state interpretations; association alone is Β.",
      "ceiling_from_boundary_check": "Γ"
    },
    {
      "subclaim_id": "SC2",
      "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated",
      "qualifying_evidence_present": "yes",
      "qualifying_evidence_citation": "PMID22196728, PMID16286007, PMID16286008, PMID12077605, PMID38724747, PMID36859550",
      "gamma_hard_rules_triggered": [
        "Peptide/nucleosome affinity or crystallographic recognition alone is capped for endogenous transcriptional inference.",
        "Co-occurrence, FRAP and localization alone are not direct output dependence.",
        "Reporter-only paired-mark results and ectopic tagged or mutant histones cannot establish endogenous necessity; this does not cap the independent loss/restoration convergence for SC2.",
        "Protein/writer loss must be separated from deposited-mark effects, residual modifications, cell-cycle redistribution and global transcription/viability collapse."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "yes",
      "perturbation_result_note": "Individual-mark/reader pathways causally regulate specified outputs across independently tested systems: Set2/Rpd3S suppresses cryptic initiation (PMID16286007,16286008), endogenous MLL2 catalytic mutation with targeted mark restoration changes selected genes (PMID38724747), and acute COMPASS loss with KDM5 buffering affects pause-release (PMID36859550). Orthogonal genetics, biochemical specificity and direct RNA outcomes exclude pure association. Contexts and residual/noncatalytic effects are mapped, supporting Ζ but not all-locus/state Η.",
      "ceiling_from_boundary_check": "Δ or higher"
    },
    {
      "subclaim_id": "SC3",
      "field_valid_perturbation_quote": "\n- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype\n- Locus-specific disruption of looping with locus-specific effect\n- Combinatorial histone-mark perturbation showing direct output dependence\n- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated",
      "qualifying_evidence_present": "no",
      "qualifying_evidence_citation": "PMID22196728, PMID16286007, PMID16286008, PMID12077605, PMID38724747, PMID36859550",
      "gamma_hard_rules_triggered": [
        "Peptide/nucleosome affinity or crystallographic recognition alone is capped for endogenous transcriptional inference.",
        "Co-occurrence, FRAP and localization alone are not direct output dependence.",
        "Reporter-only paired-mark results and ectopic tagged or mutant histones cannot establish endogenous necessity; this does not cap the independent loss/restoration convergence for SC2.",
        "Protein/writer loss must be separated from deposited-mark effects, residual modifications, cell-cycle redistribution and global transcription/viability collapse."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "BPTF dual-mark recognition and binding mutants are real, but tagged localization is not transcriptional necessity (PMID21596426). TRIM33 loss/PHD rescue establishes contextual reader dependence, without independently factorially editing endogenous K9/K18 marks (PMID22196728). Paired Polycomb targeting increases reporter silencing with at least additive and potentially synergistic effects (PMID38724747); the combination arm remains reporter-based. NURF writer deletions/truncations test recruitment, whereas full Nurf301 deletion tests transcription, leaving the exact combination-to-output bridge unresolved (PMID42165139). KAT6B loss after bivalent-specific recruitment is also a protein-function test, not factorial mark necessity (PMID39731917). Therefore Δ for the registered emergent endogenous code is not yet crossed.",
      "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": "Association is the registered evidence type; a causal experiment tests SC2/SC3 instead of upgrading a correlative existence claim by borrowing another scope."
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Δ",
      "requirement_quoted": "Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.",
      "satisfied": "yes",
      "supporting_evidence": [
        "[37] TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
        "[49] Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
        "[50] Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
        "[51] H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
        "[58] MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
        "[59] Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists."
      ],
      "what_would_cross_it": ""
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Ε",
      "requirement_quoted": "Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.",
      "satisfied": "yes",
      "supporting_evidence": [
        "[37] TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
        "[49] Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
        "[50] Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
        "[51] H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
        "[58] MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
        "[59] Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists."
      ],
      "what_would_cross_it": ""
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Ζ",
      "requirement_quoted": "Requires:\n- Independent causal tests across loci or systems\n- Specificity beyond global transcriptional collapse\n- Narrowing of key alternatives",
      "satisfied": "yes",
      "supporting_evidence": [
        "[37] TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
        "[49] Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
        "[50] Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
        "[51] H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
        "[58] MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
        "[59] Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists."
      ],
      "what_would_cross_it": ""
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Η",
      "requirement_quoted": "Requires:\n- Robust endogenous causality\n- Reproducibility across loci/cell states within scope\n- Strong evidence that the proposed mechanism is not a downstream correlate",
      "satisfied": "no",
      "supporting_evidence": [
        "[37] TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
        "[49] Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
        "[50] Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
        "[51] H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
        "[58] MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
        "[59] Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists."
      ],
      "what_would_cross_it": "Independent acute mark-specific perturbation and expression-matched restoration across prespecified cell states with unchanged cell cycle, viability and other marks would support robust endogenous generalization toward Η."
    },
    {
      "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": [
        "[37] TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.",
        "[49] Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.",
        "[50] Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.",
        "[51] H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.",
        "[58] MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.",
        "[59] Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists."
      ],
      "what_would_cross_it": "At native loci compare single-A, single-B, pair and matched controls, quantify a preregistered interaction beyond additivity, and rescue with reader architectures retaining individual affinities while selectively losing paired recognition; preserve writer scaffolds and baseline cell state."
    }
  ],
  "generalization_check": {
    "generalization_tested": "yes",
    "context_boundary_mapped": "yes",
    "internal_negative_controls": [
      "TRIM33-independent Smad homeostasis genes and ectoderm differentiation versus mesendoderm (PMID22196728).",
      "Stable Mll3/4 catalytic mutants versus protein-null cells (PMID28483418).",
      "Catalytically altered Trr rescue versus Trr protein depletion and temperature/cohesin conditions (PMID28967912).",
      "H3.3K27R with canonical H3 and other acetyl marks retained (PMID32085783).",
      "Haspin KO/RNAi/inhibition with antibody/nucleosome specificity and live-versus-fixed imaging (PMID37945563).",
      "Catalytic-dead editing controls and cis motif reporter contrasts (PMID38724747).",
      "NURF high-mark housekeeping versus low-mark developmental promoters with opposite RNA changes after full-complex loss (PMID42165139)."
    ],
    "note": "Causal mark/reader function is mapped across defined loci and states, not generalized to a deterministic code. TRIM33 gene/lineage negatives, MLL3/4 naive-versus-extraembryonic/neural states, retained acetylation, Haspin nulls and NURF promoter classes delimit the claim. A missing factorial native combination test is an identification gap, not an assertion that all combinations are nonfunctional."
  },
  "falsification_patterns_met": [
    {
      "pattern": "Perturbing the proposed feature leaves the claimed output intact",
      "evidence": "H3.3K27R and MLL3/4 catalytic changes preserve much tested transcription (PMID32085783,28483418,28967912); residual marks/state boundaries prevent universal refutation.",
      "downgrade_applied": false
    },
    {
      "pattern": "Endogenous tests contradict in vitro predictions",
      "evidence": "Haspin loss does not prevent mitotic TAF3 reader displacement despite peptide switch effects (PMID37945563). This falsifies the named switch in tested systems, not every combinatorial mechanism.",
      "downgrade_applied": false
    }
  ],
  "pitfalls_flagged": [
    {
      "pitfall": "Binding treated as regulation",
      "where": "BPTF/TAF3 affinity and structural specificity require a distinct endogenous functional endpoint."
    },
    {
      "pitfall": "Protein loss attributed to deposited marks",
      "where": "Mll3/4 and SETD1A noncatalytic functions; full NURF or KAT6B deletion does not independently manipulate mark combinations."
    },
    {
      "pitfall": "Metaphor reification",
      "where": "Code must mean a preregistered emergent interaction, not every mark-dependent recruitment."
    },
    {
      "pitfall": "Selective generalization",
      "where": "Naive ESC dispensability is not extraembryonic/neural dispensability; H3.3 is not all H3."
    },
    {
      "pitfall": "Provider citation substitution",
      "where": "Consensus broad response incorrectly attaches Ruthenburg to later catalytic-null/H3K27R claims; original records replace those pointers."
    }
  ],
  "causal_tally_audit": {
    "tally_claimed_by_document": 6,
    "tally_after_audit": 6,
    "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 higher, Δ: endogenous TRIM33 dependence/PHD rescue, 2025 bivalent-specific KAT6B recruitment and 2026 NURF writer/reader perturbations together could be interpreted as a causal combinatorial output bridge. The 2024 paired editing experiment directly changes RNA penetrance. This is the strongest pro-code case and is not reduced to mere association.",
    "case_one_rung_lower": "One rung lower, Β: histone combinations only correlate with states. That misses semisynthetic reader specificity, measurable combination enhancement, writer feedback and controlled paired RNA responses, so it is too weak even though endogenous emergent necessity remains unproved.",
    "which_rejected": "Reject Β because there is real mechanism and perturbation-supported simplified function. Reject Δ for the exact SC3 burden because reader-domain/whole-protein necessity and mark-pair reporter activity do not yet isolate an endogenous supra-additive interaction. A specific mark/reader pathway can be Δ or higher without the code claim crossing its different gate.",
    "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Perform a preregistered factorial edit of two specific native histone marks at defined TRIM33 or BPTF loci while maintaining writer proteins; pair with expression-matched reader mutants preserving each single-mark affinity but losing paired recognition, and rescue under matched signal/cell-cycle conditions."
  },
  "final_score": {
    "hsef_level": "Γ",
    "hsef_descriptor": "Mechanistically plausible, partial system support",
    "confidence": "Moderate",
    "confidence_rationale": "62 primary reports examined. Moderate rests on evidence density and reproducibility, not on reading access: the SC3 combination evidence is reporter-based or recruitment-only rather than a native-locus factorial test, two of the four independence lines rest on a single paper each, and contradicting results - H3K27ac loss, cumulative H4 charge effects and the failed TAF3 switch - remain unreconciled. Confidence bounds the evidence base, not correctness.",
    "rests_on_non_peer_reviewed_work": false,
    "rationale": "The preregistered SC3 gate returns Γ. Structural recognition, cellular recruitment and engineered reporter combinations make the mechanism plausible, while direct endogenous factorial mark dependence beyond individual effects remains unresolved. This is not a refutation of histone function: SC2 reaches Ζ on independent mark/reader perturbations with functional outcomes, and the observational SC1 stays Β on its own evidence class. Recent bivalent-reader and NURF results are included rather than inheriting the index grade uncritically."
  },
  "role_of_mechanism": {
    "classification": "reinforcing / stabilizing factor",
    "derivation_step_matched": 5,
    "derivation": "For experimentally supported mark/reader activity, sequence factors and signals provide upstream context and reader/writer circuits maintain or tune output. Rate-limiting initiation plus endogenous necessity and sufficiency across scope is not shown, so steps 3/4 do not license calling a universal code the primary driver. This role describes supported activity, not validation of emergent coding.",
    "tournament_used_as_tiebreaker": false,
    "note": "Derived from causal direction, not tournament rank."
  },
  "extended_scoring_MSD": {
    "momentum": {
      "value": "Mechanistic only",
      "artifact": "Policarpi 2024 precision loss/restoration and paired editing, 2025 bivalent/KAT6B work and 2026 NURF recruitment/RNA analysis are completed, published boundary-testing reports, not work currently being run; no ongoing programme, trial or pending result that could cross the next threshold was verified. Momentum modifies no letter.",
      "justification": "Policarpi 2024 precision loss/restoration and paired editing, 2025 bivalent/KAT6B work and 2026 NURF recruitment/RNA analysis are completed, published boundary-testing reports, not work currently being run; no ongoing programme, trial or pending result that could cross the next threshold was verified. Momentum modifies no letter."
    },
    "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": "Γ",
      "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": false,
    "prior_level": "Ranking categorical verdict visible; no prior letter used as a target",
    "prior_confidence": null,
    "prior_source": null,
    "derived_before_consulting_prior": false,
    "new_level": "Γ",
    "direction": "newly assigned",
    "what_moved_it": "Fresh primary evidence appraisal; not blinded.",
    "divergence_from_other_reviewers": null
  },
  "proposed_decisive_experiments": [
    {
      "name": "Registered boundary experiment",
      "experiment": "Perform a preregistered factorial edit of two specific native histone marks at defined TRIM33 or BPTF loci while maintaining writer proteins; pair with expression-matched reader mutants preserving each single-mark affinity but losing paired recognition, and rescue under matched signal/cell-cycle conditions.",
      "readout": "Absolute nascent transcription and single-cell output with an explicit interaction contrast, locus-resolved paired mark occupancy and reader binding",
      "critical_control": "Single-mark edits, charge-preserving controls where feasible, catalytic-dead recruitment, scaffold-preserving mutants, cell cycle/viability/replication-stress measurements, and unaffected prespecified loci",
      "supporting_result": "Combination-selective loss abolishes a reproducible interaction beyond additive effects and a paired-reading-competent rescue restores it at native loci",
      "falsifying_result": "RNA effects reduce to single-mark action, writer scaffolding, charge, secondary cell-state change or promoter sequence despite loss of paired recognition"
    }
  ],
  "knowledge_gaps": [
    {
      "name": "Gap 1",
      "statement": "Test native-locus factorial combinations with an explicit additive null rather than calling higher affinity synergy.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 2",
      "statement": "Separate mark identity from nucleosome geometry/asymmetry, DNA motifs and general reader avidity.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 3",
      "statement": "Use combination-selective reader mutants with single-mark affinity, folding and expression controls.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 4",
      "statement": "Compare rapid mark loss with chronic catalytic-null compensation and retained canonical histone variants.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 5",
      "statement": "Map MLL3/4 effects prospectively across embryonic, extraembryonic and neural states.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 6",
      "statement": "Distinguish initiation, polymerase pause-release, elongation and final RNA abundance.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 7",
      "statement": "Measure local paired occupancy quantitatively rather than overlapping bulk ChIP peaks.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 8",
      "statement": "Replicate NURF recruitment-to-transcription coupling with writer/reader-specific rescue rather than full complex loss alone.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 9",
      "statement": "Resolve KAT6B combination-specific recruitment versus its broader developmental functions.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 10",
      "statement": "Finish unavailable bodies/supplements and linked correction details before a complete-paper publication claim.",
      "relevance": "Limits mechanism identification or scope."
    }
  ],
  "review_metadata": {
    "review_date": "2026-10-08",
    "reviewer": "Codex",
    "evidence_base_note": "62 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; bounded critical review, not exhaustive systematic review.",
    "literature_tools_available": true,
    "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; matched primary leads were resolved to original records before counting. See scispace-leads.json.",
    "skill_version": "5.3",
    "validator_run": "exact archived v5.3 validator 2.3; see validator.txt",
    "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.",
    "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible."
  },
  "is_calibration_entry": {
    "value": false,
    "entry_role": "not_calibration",
    "blind_graded": null,
    "completed_blinded_calibration": false,
    "expected_band_sealed_at": "",
    "target_sha256": "",
    "target_authorship": "not applicable",
    "target_author_saw_review": null,
    "future_run_status": "not prepared",
    "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed."
  },
  "upper_ladder_check": {
    "final_level_below_zeta": true,
    "equivalents_considered": [
      {
        "kind": "mendelian_randomization",
        "available": false,
        "why_not_sufficient": "Endogenous degrons, catalytic knock-ins, selective reader rescue, dose/context contrasts and targeted native-locus restoration were considered as live upper-ladder routes. They support SC2 convergence without RCT requirements. For SC3, association/binding, writer scaffolding, retained marks and reporter combination effects leave endogenous emergent output unresolved; a weak evidence class is not re-capped over an independently identified causal set."
      },
      {
        "kind": "natural_experiment",
        "available": false,
        "why_not_sufficient": "Endogenous degrons, catalytic knock-ins, selective reader rescue, dose/context contrasts and targeted native-locus restoration were considered as live upper-ladder routes. They support SC2 convergence without RCT requirements. For SC3, association/binding, writer scaffolding, retained marks and reporter combination effects leave endogenous emergent output unresolved; a weak evidence class is not re-capped over an independently identified causal set."
      },
      {
        "kind": "dose_response_across_populations",
        "available": false,
        "why_not_sufficient": "Endogenous degrons, catalytic knock-ins, selective reader rescue, dose/context contrasts and targeted native-locus restoration were considered as live upper-ladder routes. They support SC2 convergence without RCT requirements. For SC3, association/binding, writer scaffolding, retained marks and reporter combination effects leave endogenous emergent output unresolved; a weak evidence class is not re-capped over an independently identified causal set."
      },
      {
        "kind": "withdrawal_rechallenge",
        "available": false,
        "why_not_sufficient": "Endogenous degrons, catalytic knock-ins, selective reader rescue, dose/context contrasts and targeted native-locus restoration were considered as live upper-ladder routes. They support SC2 convergence without RCT requirements. For SC3, association/binding, writer scaffolding, retained marks and reporter combination effects leave endogenous emergent output unresolved; a weak evidence class is not re-capped over an independently identified causal set."
      },
      {
        "kind": "therapeutic_perturbation_hard_endpoint",
        "available": false,
        "why_not_sufficient": "Endogenous degrons, catalytic knock-ins, selective reader rescue, dose/context contrasts and targeted native-locus restoration were considered as live upper-ladder routes. They support SC2 convergence without RCT requirements. For SC3, association/binding, writer scaffolding, retained marks and reporter combination effects leave endogenous emergent output unresolved; a weak evidence class is not re-capped over an independently identified causal set."
      }
    ],
    "convergence_present": true,
    "cap_reapplied_to_convergent_set": false
  },
  "provenance_header": {
    "sources_total": 62,
    "claims_total": 66,
    "claims_verified": 66,
    "claims_unverified": 0,
    "claims_contradicted": 0,
    "tier_a_sources": 62,
    "generated_by": "Codex; HSEF v5.3",
    "gate_passed": true
  },
  "claims": [
    {
      "id": "C1",
      "text": "Catalytic-deficient Trr rescues fly viability; enhancer methylation changes have small transcriptional effects with stress-dependent exceptions. Does not make all marks dispensable; genomic transgene rescue, residual marks, stress phenotypes and mammalian lineage limits matter.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        1
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods & Materials, 2:Main text. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C2",
      "text": "Trim24 couples unmethylated H3K4 recognition to local restriction of p53 chromatin opening and gene activation. A cofactor-context mechanism is not a factorial demonstration of a multi-mark instruction code.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        2
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C3",
      "text": "H3Q5ser enhances TAF3 readout and inhibits selected H3K4 erasers without equally changing all readers or writers. Binding and turnover effects do not establish endogenous combination-specific transcription beyond individual marks.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        3
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C4",
      "text": "TAF3 PHD structure explains H3K4me3 recognition and antagonism by H3R2 methylation. A proposed methyl-methyl switch remains biochemical without locus-specific functional testing here.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        4
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C5",
      "text": "NURF recognizes triply modified H3; writer deletions/reader-domain truncation impair stable recruitment; whole Nurf301 mutants alter nucleosome positions and transcript output. Recruitment and whole-complex loss are distinct tests; high-mark housekeeping promoters increase expression after NURF loss. No endogenous factorial single/pair/triple transcription rescue isolates emergent code output.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        5
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Results:paragraph4, 2:Results:paragraph8, 2:Results:paragraph13, 2:Results:paragraph16, 2:Results:paragraph17, 2:Results:paragraph19, 2:Results:paragraph22, 2:Results:paragraph24, 2:Results:paragraph26, 2:Results:paragraph27. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C6",
      "text": "BPTF distinguishes H3K4me3/H4K16ac at nucleosome level and binding-pocket/linker mutants impair tagged BPTF localization. No endogenous transcriptional necessity test; ectopic tagged BPTF coexists with native protein and free-peptide binding lacks detectable allostery.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        6
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:RESULTS:paragraph1, 0:RESULTS:paragraph2, 0:RESULTS:paragraph4, 0:RESULTS:paragraph6, 0:RESULTS:paragraph10, 0:RESULTS:paragraph12, 0:RESULTS:paragraph13, 0:RESULTS:paragraph14. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C7",
      "text": "TAF3 PHD has a defined surface recognizing H3Q5ser alongside H3K4me3. Structural specificity does not demonstrate endogenous combinatorial transcriptional dependence.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        7
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C8",
      "text": "KMT2C/D catalytic activity supports H3K4me1 and promoter-enhancer contacts at a subset of induced enhancers; KMT2B depletion worsens defects at retained sites. Contacts are not alone causal transcription; redundant writers and enhancer subclasses limit a universal activation rule.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        8
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C9",
      "text": "BAF and MLL4 reciprocally support recruitment and lineage-factor-dependent enhancer activation; PBAF provides a context contrast. Protein depletion does not separate catalytic marks from coactivator scaffolds or establish combination synergy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        9
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C10",
      "text": "MLL4 supports cell fate transition and p300 recruitment while maintenance/self-renewal can persist without it. The protein rather than its methylation activity controls p300 recruitment; no strict two-mark code follows.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        10
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C11",
      "text": "Polycomb directly binds and inhibits CBP, linking histone acetylation to protein interaction regulation. CBP autoacetylation, protein contacts and overexpression confound attribution to a histone combination alone.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        11
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C12",
      "text": "Eliminating MLL3/4 catalysis impairs extraembryonic lineages and gastrulation while embryonic-lineage differentiation is less dependent. Contradicts unlimited dispensability and unlimited necessity alike; lineage function does not isolate a combinatorial reader code.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        12
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C13",
      "text": "Mll4 is needed to exit naive pluripotency but its catalytic activity is dispensable; LSD1 depletion rescues Mll4-null transition. Co-regulator compensation supports a regulatory axis rather than proof that marks never act causally.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        13
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C14",
      "text": "SETD1A FLOS/cyclin-K function controls survival and DNA damage response despite dispensable SET catalytic domain. A noncatalytic dependency cannot be counted as evidence for histone methylation or mark-combination causality.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        14
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C15",
      "text": "EED/EZH2 structures explain allosteric stimulation by H3K27me3 and catalytic organization. Cell-free structural feedback is capped for endogenous causal output.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        15
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C16",
      "text": "Different H3K27 methylation states associate with distinct genomic functions and perturbations affect transcription/enhancer fidelity. Complex loss and secondary H3K36 interactions make individual-state specificity and combinatorial effects difficult to isolate.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        16
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C17",
      "text": "H3K4me3/H3K36 methylation inhibit PRC2 while H3K27me3 stimulates it. Biochemical writer crosstalk establishes plausibility, not transcriptional instruction at endogenous loci.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        17
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C18",
      "text": "Recruiting p300 catalytic core to selected promoters/enhancers activates target genes with localized H3K27ac. Ectopic recruitment and multiple p300 substrates do not isolate one residue or an endogenous combination-specific mechanism.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        18
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C19",
      "text": "Sumoylation recruits Set3 HDAC through Cpr1 and cooperates with H2Bub/H3K4me2 to suppress cryptic transcription. A sequential crosstalk pathway does not by itself define emergent information in simultaneous mark combinations.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        19
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C20",
      "text": "Site-specific H2B ubiquitination directly stimulates intranucleosomal Dot1L H3K79 methylation. Purified writer activity is not endogenous transcriptional causality.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        20
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C21",
      "text": "Dot1L contacts ubiquitin and the acidic patch in a methylation-ready configuration. Structural activation does not establish a combinatorial gene-output code.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        21
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C22",
      "text": "H2Bub tracks polymerase advance and elongation rate more closely than slower methyl marks. A cotranscriptional readout is not an upstream instruction; pausing associations do not establish primacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        22
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C23",
      "text": "COMPASS bridges ubiquitin and nucleosome contacts to stimulate H3K4 methylation across histone tails. Reconstituted crosstalk does not specify endogenous transcriptional output beyond constituent effects.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        23
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C24",
      "text": "H4K16ac and H2Bub cooperate in regulating Dot1 H3K79 methylation and silencing. Writer stimulation and epigenetic maintenance are not a general deterministic code; full report access remains abstract-only here.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        24
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C25",
      "text": "Nucleosome contacts allosterically activate Eaf3 through Rco1; interface mutations preserve complex integrity but impair function. Multivalent chromatin engagement includes unmodified structural contacts; not necessarily a specific mark-combination instruction.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        25
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C26",
      "text": "Histone-residue perturbations map regulatory associations with methylases and deacetylases. Mutations alter residue chemistry and expression similarity does not by itself establish epistasis or specific combinatorial reading.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        26
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C27",
      "text": "Engineered methylation states show shared cryptic-transcription suppression and a distinct H3K36me3-associated Bur1/FACT function. Redundancy among states limits a one-state/one-output vocabulary; stress and yeast scope remain bounded.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        27
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C28",
      "text": "Reader/writer/scaffold multivalency promotes dense, DNase-resistant H3K9-methylated droplets excluding TFIIB. In vitro droplets and exclusion do not establish endogenous phase separation or transcriptional instruction.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        28
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C29",
      "text": "DNMT3B recognizes H3K36me3 through a defined aromatic/water pocket; a disease mutation disrupts affinity. Structural model is not a direct endogenous transcriptional or combinatorial causal test.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        29
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C30",
      "text": "TAF3/TAF5 and other H3K4 readers still leave mitotic chromosomes when H3T3ph is absent; adjacent H3K4me2/3 suppresses H3T3 phosphorylation. Refutes this proposed cellular switch in tested cells, not all methyl-phospho switching; CIDOP is an isolated-chromatin assay.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        30
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph13, 1:Results:paragraph16, 1:Results:paragraph3, 1:Results:paragraph4, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph17, 1:Results:paragraph20. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C31",
      "text": "Developmental promoters carry regional H3K4/H3K27 bivalency and low expression with sequence associations. Regional coexistence and proposed poising are not factorial endogenous causal instruction.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        31
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C32",
      "text": "Bivalent marks occupy opposite H3 tails; asymmetric placement permits PRC2 activity unlike symmetric placement. Nucleosomal asymmetry changes biochemistry; functional poising requires separate perturbation evidence.",
      "carries_number": true,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        32
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C33",
      "text": "Asymmetric bivalent nucleosomes recruit KAT6B beyond either mark alone; KAT6B loss blocks neuronal differentiation. Reader-complex loss is not factorial mark removal with rescue; developmental failure need not prove the combination itself specifies output.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        33
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C34",
      "text": "Directly detects co-modified nucleosomes and state-specific effects of enzyme perturbation. Technology and state abundance do not establish causal combinations beyond additive effects.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        34
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C35",
      "text": "TRIM24 tandem reader recognizes H3K4me0/H3K23ac and supports estrogen-dependent gene activation. Patient survival is associative; reader/protein effects do not independently manipulate both endogenous marks.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        35
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C36",
      "text": "H3K18ac and TRIM33 accessibility prime nodal responses in embryoid bodies with a contrasting ESC context. p300/HDAC1 regulate multiple substrates; the specific two-mark interaction is not independently factorially tested.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        36
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C37",
      "text": "TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback. Positive threshold crossing is for reader-dependent contextual gene activation, not proof of supra-additive endogenous mark combinations. PHD deletion and writer feedback remain alternatives.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        37
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph13, 1:Results:paragraph15, 1:Results:paragraph16, 1:Results:paragraph17, 1:Results:paragraph18, 1:Results:paragraph20. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C38",
      "text": "H3K4me3, acetylation and TATA DNA synergize in TFIID binding, and TAF3 PHD supports rapid gene induction. Binding synergy with DNA is not factorial endogenous histone-only output dependence.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        38
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C39",
      "text": "H3K4me3 loss reduces TFIID/promoter activity in subsets; R2 methylation antagonizes and acetylation potentiates binding. Selective single-mark effects and transient coactivation do not establish a general multi-mark code.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        39
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C40",
      "text": "H3K4me3-TAF3 supports PIC assembly and selective p53 activation, cooperatively with TATA elements. DNA/mark cooperation and cellular context do not demonstrate histone-combination causality.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        40
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C41",
      "text": "H3S10 phosphorylation ejects HP1 despite persistent H3K9me3; Aurora-B inhibition retains HP1 in mitosis. HP1 relocation is a protein/chromatin endpoint, not direct combination-specific transcriptional output.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        41
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C42",
      "text": "H3K9me3S10ph marks mitotic heterochromatin and blocked phosphorylation prevents HP1 release. Supports a reader-binding switch but not the registered transcription code; mitotic kinase pleiotropy needs controls.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        42
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C43",
      "text": "All H4 lysine-mutant combinations separate a specific K16 effect from cumulative K5/K8/K12 transcription effects. Arginine substitutes charge/nonmodifiable chemistry, not acetylation alone; findings are yeast H4 scope rather than universal refutation.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        43
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C44",
      "text": "Stable catalytic-null Mll3/4 proteins retain enhancer transcription despite mark loss; protein deletion suppresses polymerase/eRNA and nearby genes. Residual H3K4me1 and naive ESC state constrain dispensability; protein dependence is not mark dependence.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        44
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph4, 1:Results:paragraph6, 1:Results:paragraph8, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph13. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C45",
      "text": "MLL3/4-dependent H3K4me1 contributes to cohesin recruitment, contacts and differentiation-linked gene activation. Mark/protein perturbation and contacts need specificity; linked erratum attached and its detailed correction was not independently examined.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        45
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C46",
      "text": "Mutating both H3.3 genes sharply reduces enhancer H3K27ac while many transcripts/accessibility features persist. Canonical H3 remains modifiable and other acetyl marks remain; no total-H3K27ac or all-context dispensability follows.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        46
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results and discussion:paragraph0, 1:Results and discussion:paragraph2, 1:Results and discussion:paragraph3, 1:Results and discussion:paragraph4, 1:Results and discussion:paragraph6, 1:Results and discussion:paragraph7, 1:Results and discussion:paragraph8. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C47",
      "text": "Many enhancers lose changing H3K4me1/H3K27ac without preventing activation of nearby genes; stable and dynamic sites differ. Nearest-gene assignment and alternative activating pathways constrain inference; this is not proof all enhancer marks are inert.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        47
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C48",
      "text": "Eaf3 recognition of methylated H3K36 supports coding-region deacetylation and suppresses internal initiation. A transcription-coupled reader pathway is not necessarily simultaneous combinatorial instruction.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        48
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C49",
      "text": "Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts. Establishes a causal mark/reader pathway at coding regions, not a rich deterministic multi-mark code.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        49
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C50",
      "text": "Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence. Shares yeast pathway biology with other reports; distinct laboratory work is not proof of universal combinatorial encoding.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        50
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C51",
      "text": "H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing. Residue mutations and Rad6 pleiotropy constrain specificity; ordered writer crosstalk is distinct from emergent output encoding.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        51
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C52",
      "text": "Regulated H2B deubiquitination supports GAL10 activation and coupled H3K4 methylation. SAGA also acetylates and scaffolds transcription; multiple functions prevent code-only attribution.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        52
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C53",
      "text": "EED recognizes repressive methyl-lysines to stimulate PRC2; binding mutants impair methylation/development. Feedback propagation does not alone specify combinatorial transcription outputs.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        53
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C54",
      "text": "Acetylated/methylated residue mutants show growth interaction but largely independent gene-expression effects and different Sir4 binding. Interdependence is phenotype-specific; residue replacements do not selectively erase one chemical mark.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        54
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C55",
      "text": "Acetylation precedes CARM1 methylation and facilitates binding/activity at estrogen-responsive chromatin. Exogenous CBP sufficiency and ordered deposition do not prove endogenous supra-additive combination output.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        55
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C56",
      "text": "H3K4me3Q5ser occurs in vivo, enhances TFIID interaction, and nonserotonylatable ectopic H3 alters differentiation/transcription. Ectopic mutant and writer multiple substrates cap inference to endogenous combinatorial necessity.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        56
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C57",
      "text": "Twelve modifications form broad co-occurring gradients rather than many discrete deterministic states. Observational mapping cannot disprove specific causal combinations elsewhere; continuous patterns may remain functional.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        57
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C58",
      "text": "MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance. Paired-mark result is in engineered reporters, at least additive and potentially synergistic; it does not prove endogenous beyond-additive code necessity.",
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      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C59",
      "text": "Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists. Shared SET1/COMPASS functions and proliferation effects limit perfect specificity; linked corrections remain attached, not separate primary counts.",
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      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C60",
      "text": "Expression associations depend on mark combinations; many mark changes remain uncoupled from transcript changes. This is observational combinatorial association rather than intervention-driven code validation.",
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      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C61",
      "text": "H3K4me1/MLL3/4 and p300/H3K27ac perturbations affect eviction and eRNA asymmetrically at beta-globin enhancers. Enzyme-domain lesions affect multiple outputs/substrates; differing individual roles do not establish supra-additivity.",
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      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "C62",
      "text": "H3K4ac relates to eviction/transcription and can overlap redundantly with H3K27ac in eRNA regulation. p300 and MLL3/4 affect many marks; interdependence and redundancy are distinct from a strict code.",
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      "verified_on": "2026-10-09",
      "note": ""
    },
    {
      "id": "CSC1",
      "text": "Genome-wide and single-nucleosome patterns reproducibly track transcription and developmental state (PMID16630819,27151869,17997276,16122352). This existence subclaim is supported by association, with continuous gradients and asymmetric nucleosomes limiting discrete-state interpretations; association alone is Β.",
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    {
      "id": "CSC2",
      "text": "Individual-mark/reader pathways causally regulate specified outputs across independently tested systems: Set2/Rpd3S suppresses cryptic initiation (PMID16286007,16286008), endogenous MLL2 catalytic mutation with targeted mark restoration changes selected genes (PMID38724747), and acute COMPASS loss with KDM5 buffering affects pause-release (PMID36859550). Orthogonal genetics, biochemical specificity and direct RNA outcomes exclude pure association. Contexts and residual/noncatalytic effects are mapped, supporting Ζ but not all-locus/state Η.",
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    },
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      "id": "CSC3",
      "text": "BPTF dual-mark recognition and binding mutants are real, but tagged localization is not transcriptional necessity (PMID21596426). TRIM33 loss/PHD rescue establishes contextual reader dependence, without independently factorially editing endogenous K9/K18 marks (PMID22196728). Paired Polycomb targeting increases reporter silencing with at least additive and potentially synergistic effects (PMID38724747); the combination arm remains reporter-based. NURF writer deletions/truncations test recruitment, whereas full Nurf301 deletion tests transcription, leaving the exact combination-to-output bridge unresolved (PMID42165139). KAT6B loss after bivalent-specific recruitment is also a protein-function test, not factorial mark necessity (PMID39731917). Therefore Δ for the registered emergent endogenous code is not yet crossed.",
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    {
      "id": "CH",
      "text": "Histone marks and their readers have causal functions; a general endogenous combinatorial transcription code remains below the direct-output boundary.",
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      "citation": "Rickels R, Herz HM, Sze CC et al. Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nature genetics. 2017.",
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    },
    {
      "n": 3,
      "citation": "Zhao S, Chuh KN, Zhang B et al. Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout. Proceedings of the National Academy of Sciences of the United States of America. 2021.",
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    },
    {
      "n": 4,
      "citation": "van Ingen H, van Schaik FM, Wienk H et al. Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3. Structure (London, England : 1993). 2008.",
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    },
    {
      "n": 5,
      "citation": "Kwon SY, Jang B, Grisan V et al. Combinatorial histone modifications direct ATP-dependent chromatin remodeling by NURF to promoter-proximal nucleosomes. Nucleic acids research. 2026.",
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      "pmid": "42165139",
      "doi": "10.1093/nar/gkag494",
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        "CH"
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    },
    {
      "n": 6,
      "citation": "Ruthenburg AJ, Li H, Milne TA et al. Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions. Cell. 2011.",
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        "CH"
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    },
    {
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      "citation": "Pulido-Cortés L, Gielingh H, Thijssen V et al. Molecular determinants for recognition of serotonylated chromatin. Nucleic acids research. 2025.",
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        "CSC3"
      ]
    },
    {
      "n": 8,
      "citation": "Kubo N, Chen PB, Hu R et al. H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation. Molecular cell. 2024.",
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      "carries_claims": [
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        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 9,
      "citation": "Park YK, Lee JE, Yan Z et al. Interplay of BAF and MLL4 promotes cell type-specific enhancer activation. Nature communications. 2021.",
      "tier": "A",
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      "doi": "10.1038/s41467-021-21893-y",
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      "carries_claims": [
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        "CSC2",
        "CSC3"
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    },
    {
      "n": 10,
      "citation": "Wang C, Lee JE, Lai B et al. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proceedings of the National Academy of Sciences of the United States of America. 2016.",
      "tier": "A",
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      "doi": "10.1073/pnas.1606857113",
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      "carries_claims": [
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        "CSC2",
        "CSC3"
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    },
    {
      "n": 11,
      "citation": "Tie F, Banerjee R, Fu C et al. Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain. Proceedings of the National Academy of Sciences of the United States of America. 2016.",
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      "doi": "10.1073/pnas.1515465113",
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      "carries_claims": [
        "C11",
        "CSC2",
        "CSC3"
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    },
    {
      "n": 12,
      "citation": "Xie G, Lee JE, Senft AD et al. MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner. Nature genetics. 2023.",
      "tier": "A",
      "kind": "primary",
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      "doi": "10.1038/s41588-023-01356-4",
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      "carries_claims": [
        "C12",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 13,
      "citation": "Cao K, Collings CK, Morgan MA et al. An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells. Science advances. 2018.",
      "tier": "A",
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      "doi": "10.1126/sciadv.aap8747",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29404406/",
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      "carries_claims": [
        "C13",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 14,
      "citation": "Hoshii T, Cifani P, Feng Z et al. A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell. 2018.",
      "tier": "A",
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      "doi": "10.1016/j.cell.2018.01.032",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29474905/",
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      ],
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      "opened_on": "2026-10-09",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C14",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 15,
      "citation": "Jiao L, Liu X et al. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science (New York, N.Y.). 2015.",
      "tier": "A",
      "kind": "primary",
      "pmid": "26472914",
      "doi": "10.1126/science.aac4383",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26472914/",
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      "study_id": "PMID26472914",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C15",
        "CSC3"
      ]
    },
    {
      "n": 16,
      "citation": "Ferrari KJ, Scelfo A, Jammula S et al. Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity. Molecular cell. 2014.",
      "tier": "A",
      "kind": "primary",
      "pmid": "24289921",
      "doi": "10.1016/j.molcel.2013.10.030",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24289921/",
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      ],
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      "study_id": "PMID24289921",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C16",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 17,
      "citation": "Schmitges FW, Prusty AB, Faty M et al. Histone methylation by PRC2 is inhibited by active chromatin marks. Molecular cell. 2011.",
      "tier": "A",
      "kind": "primary",
      "pmid": "21549310",
      "doi": "10.1016/j.molcel.2011.03.025",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21549310/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C17",
        "CSC3"
      ]
    },
    {
      "n": 18,
      "citation": "Hilton IB, D'Ippolito AM, Vockley CM et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nature biotechnology. 2015.",
      "tier": "A",
      "kind": "primary",
      "pmid": "25849900",
      "doi": "10.1038/nbt.3199",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25849900/",
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      "opened": true,
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      "study_id": "PMID25849900",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
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        "CSC2",
        "CSC3"
      ]
    },
    {
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      "citation": "Ryu HY, Zhao D, Li J et al. Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation. Nucleic acids research. 2020.",
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      "citation": "McGinty RK, Kim J, Chatterjee C et al. Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation. Nature. 2008.",
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      "citation": "Fuchs G, Hollander D, Voichek Y et al. Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate. Genome research. 2014.",
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      "citation": "Worden EJ, Zhang X, Wolberger C et al. Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome. eLife. 2020.",
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    {
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    {
      "n": 28,
      "citation": "Wang L, Gao Y, Zheng X et al. Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism. Molecular cell. 2019.",
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      "citation": "Rondelet G, Dal Maso T, Willems L et al. Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. Journal of structural biology. 2016.",
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      "citation": "Harris RJ, Heer M, Levasseur MD et al. Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation. Nature communications. 2023.",
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      "citation": "Bernstein BE, Mikkelsen TS, Xie X et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006.",
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      "citation": "Shema E, Jones D, Shoresh N et al. Single-molecule decoding of combinatorially modified nucleosomes. Science (New York, N.Y.). 2016.",
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      "citation": "Tsai WW, Wang Z, Yiu TT et al. TRIM24 links a non-canonical histone signature to breast cancer. Nature. 2010.",
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      "citation": "Xi Q, Wang Z, Zaromytidou AI et al. A poised chromatin platform for TGF-β access to master regulators. Cell. 2011.",
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      "citation": "Vermeulen M, Mulder KW, Denissov S et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell. 2007.",
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      "n": 41,
      "citation": "Fischle W, Tseng BS, Dormann HL et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature. 2005.",
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      "n": 42,
      "citation": "Hirota T, Lipp JJ, Toh BH et al. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature. 2005.",
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      "citation": "Dion MF, Altschuler SJ, Wu LF et al. Genomic characterization reveals a simple histone H4 acetylation code. Proceedings of the National Academy of Sciences of the United States of America. 2005.",
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      "citation": "Dorighi KM, Swigut T, Henriques T et al. Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation. Molecular cell. 2017.",
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    {
      "n": 45,
      "citation": "Yan J, Chen SA, Local A et al. Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers. Cell research. 2018.",
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    {
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      "citation": "Zhang T, Zhang Z, Dong Q et al. Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells. Genome biology. 2020.",
      "tier": "A",
      "kind": "primary",
      "pmid": "32085783",
      "doi": "10.1186/s13059-020-01957-w",
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        "C46",
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        "CSC3",
        "CH"
      ]
    },
    {
      "n": 47,
      "citation": "Boileau RM, Chen KX, Blelloch R et al. Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during embryonic stem cell differentiation. Genome biology. 2023.",
      "tier": "A",
      "kind": "primary",
      "pmid": "36869380",
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      "access_depth": "abstract_metadata",
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      "carries_claims": [
        "C47",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 48,
      "citation": "Joshi AA, Struhl K et al. Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation. Molecular cell. 2005.",
      "tier": "A",
      "kind": "primary",
      "pmid": "16364921",
      "doi": "10.1016/j.molcel.2005.11.021",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16364921/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C48",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 49,
      "citation": "Carrozza MJ, Li B, Florens L et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005.",
      "tier": "A",
      "kind": "primary",
      "pmid": "16286007",
      "doi": "10.1016/j.cell.2005.10.023",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16286007/",
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      "opened_on": "2026-10-09",
      "status_checked_on": "2026-10-09",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C49",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 50,
      "citation": "Keogh MC, Kurdistani SK, Morris SA et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell. 2005.",
      "tier": "A",
      "kind": "primary",
      "pmid": "16286008",
      "doi": "10.1016/j.cell.2005.10.025",
      "url": "https://pubmed.ncbi.nlm.nih.gov/16286008/",
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        "C50",
        "CSC2",
        "CSC3"
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    },
    {
      "n": 51,
      "citation": "Sun ZW, Allis CD et al. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002.",
      "tier": "A",
      "kind": "primary",
      "pmid": "12077605",
      "doi": "10.1038/nature00883",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12077605/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C51",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 52,
      "citation": "Daniel JA, Torok MS, Sun ZW et al. Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. The Journal of biological chemistry. 2004.",
      "tier": "A",
      "kind": "primary",
      "pmid": "14660634",
      "doi": "10.1074/jbc.C300494200",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C52",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 53,
      "citation": "Margueron R, Justin N, Ohno K et al. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 2009.",
      "tier": "A",
      "kind": "primary",
      "pmid": "19767730",
      "doi": "10.1038/nature08398",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19767730/",
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      "carries_claims": [
        "C53",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 54,
      "citation": "Jin Y, Rodriguez AM, Wyrick JJ et al. Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae. Genetics. 2009.",
      "tier": "A",
      "kind": "primary",
      "pmid": "19087956",
      "doi": "10.1534/genetics.108.098897",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19087956/",
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      "carries_claims": [
        "C54",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 55,
      "citation": "Daujat S, Bauer UM, Shah V et al. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Current biology : CB. 2002.",
      "tier": "A",
      "kind": "primary",
      "pmid": "12498683",
      "doi": "10.1016/s0960-9822(02)01387-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12498683/",
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      "carries_claims": [
        "C55",
        "CSC2",
        "CSC3"
      ]
    },
    {
      "n": 56,
      "citation": "Farrelly LA, Thompson RE, Zhao S et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature. 2019.",
      "tier": "A",
      "kind": "primary",
      "pmid": "30867594",
      "doi": "10.1038/s41586-019-1024-7",
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      "carries_claims": [
        "C56",
        "CSC2",
        "CSC3"
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    },
    {
      "n": 57,
      "citation": "Liu CL, Kaplan T, Kim M et al. Single-nucleosome mapping of histone modifications in S. cerevisiae. PLoS biology. 2005.",
      "tier": "A",
      "kind": "primary",
      "pmid": "16122352",
      "doi": "10.1371/journal.pbio.0030328",
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      "carries_claims": [
        "C57",
        "CSC1",
        "CSC3"
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    },
    {
      "n": 58,
      "citation": "Policarpi C, Munafò M, Tsagkris S et al. Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications. Nature genetics. 2024.",
      "tier": "A",
      "kind": "primary",
      "pmid": "38724747",
      "doi": "10.1038/s41588-024-01706-w",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38724747/",
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        "CSC2",
        "CSC3",
        "CH"
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    },
    {
      "n": 59,
      "citation": "Wang H, Fan Z, Shliaha PV et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature. 2023.",
      "tier": "A",
      "kind": "primary",
      "pmid": "36859550",
      "doi": "10.1038/s41586-023-05780-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36859550/",
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      "carries_claims": [
        "C59",
        "CSC2",
        "CSC3",
        "CH"
      ]
    },
    {
      "n": 60,
      "citation": "Fischer JJ, Toedling J, Krueger T et al. Combinatorial effects of four histone modifications in transcription and differentiation. Genomics. 2008.",
      "tier": "A",
      "kind": "primary",
      "pmid": "17997276",
      "doi": "10.1016/j.ygeno.2007.08.010",
      "url": "https://pubmed.ncbi.nlm.nih.gov/17997276/",
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      "study_id": "PMID17997276",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "carries_claims": [
        "C60",
        "CSC1",
        "CSC3"
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    },
    {
      "n": 61,
      "citation": "Kang Y, Kim YW, Kang J et al. Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2021.",
      "tier": "A",
      "kind": "primary",
      "pmid": "34309923",
      "doi": "10.1096/fj.202100488R",
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      "carries_claims": [
        "C61",
        "CSC2",
        "CSC3"
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    },
    {
      "n": 62,
      "citation": "Kang J, Kang Y, Kim A et al. Histone H3K4ac, as a marker of active transcription start sites and enhancers, plays roles in histone eviction and RNA transcription. Biochimica et biophysica acta. Gene regulatory mechanisms. 2024.",
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        "sources": [
          49,
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        "excludes_error": "Independent genetic and RNA studies exclude purely descriptive ChIP, while the shared Set2/Rpd3S pathway is one biological family."
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