# HSEF v5.3 review: Histone Code Hypothesis

> Sources: 62 primary reports; claims: 66; verified: 66; unverified: 0. Verification is bounded attribution. Access: 9 partial-body and 53 complete abstract/status examinations. Literature cutoff: 2026-10-08; source examination UTC date: 2026-10-09. No complete-paper audit or blinded calibration claimed.

> **Adversarial review:** Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 4 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: **Approved as revised.**

## AT A GLANCE

**Histone marks and their readers have causal functions; a general endogenous combinatorial transcription code remains below the direct-output boundary.**

| Level | Confidence | Causal role | Momentum | Stability | Divergence |
|---|---|---|---|---|---|
| Γ — Mechanistically plausible, partial system support | Moderate | reinforcing / stabilizing factor | Mechanistic only | Stable | Contested |

**Deciding 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.

**Belief versus evidence:** 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.

**Best-supported rival:** Context-defined individual-mark functions. 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.

## COMPETING MECHANISTIC MODELS

**Rank 1: Context-defined individual-mark functions (Ζ).** Individual marks and recruited factors tune transcription at selected loci rather than encoding a universal vocabulary. 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 2: Reader-writer feedback and state stabilization (Ε).** Multivalent readers and writer feedback stabilize states initiated by sequence factors and signaling. 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 3: Strict combinatorial instruction (Γ).** Specific mark combinations encode emergent transcription outputs beyond constituent effects. 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 4: Cumulative acetylation and charge effects (Ε).** Some acetylation effects follow total charge/accessibility rather than site-combination identity. 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 5: Transcriptional consequence and metabolic readout (Β).** Some marks record ongoing transcription or metabolic context instead of independently instructing it. 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).

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

## FULL REVIEW

### Registered claim and scope

Specific combinations of histone modifications are read as a combinatorial code that causally specifies transcriptional outputs beyond the effects of individual marks.

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.

Selection: public-interest rank 36 from the editorial ranking compiled 2026-09-23; categorical prior verdicts were visible. Private fresh review; earlier documents are preserved.

### Evidence and causal interpretation

The review distinguishes three burdens. Reproducible mark-state association is widespread, individual mark/reader causality is supported in several defined systems, and emergent combinatorial transcription requires a further test. A label such as histone code is not a substitute for that test. The 62-paper primary set includes support, dispensability, causal alternatives and recent developments through the registered literature cutoff.

Ruthenburg shows nucleosome-level discrimination of H3K4me3/H4K16ac, stronger than promiscuous peptide binding (PMID21596426). Free-peptide reciprocal titrations do not detect allostery; constrained bivalent geometry and the linker matter. Tagged BPTF mutant localization occurs with native BPTF still present, and transcription is not the tested necessity endpoint. This is convincing molecular recognition without automatically crossing the emergent endogenous-output boundary.

TRIM24 and TRIM33 demonstrate useful context-sensitive readers (PMID21164480,22196728). TRIM33-null/depleted cells lose mesendodermal responses; wild-type but not PHD-deleted rescue restores activation and Smad4 binding. Other Smad targets and ectoderm differentiation provide negative controls. Dual K9me3/K18ac enhances peptide affinity and both marks occur on native nucleosomes, but the same study also shows Smad-driven acetylation feedback. The combination itself is not independently edited factorially at the native promoters. The later EB/ESC comparison maps another context boundary (PMID31564646).

The 2026 NURF study is a serious addition to older code assessments (PMID42165139). Triply modified H3 increases binding, Gcn5/Jil1 loss and reader-domain truncation impair stable recruitment, and primary hemocyte Nurf301 loss changes nucleosome position and RNA output. Yet high-mark housekeeping promoters have modestly increased RNA after complex loss while low-mark developmental promoters decrease. Recruitment perturbations and whole-complex transcription perturbations are separate arms, so a unique native combination-to-output interaction remains to be isolated.

Catalytic-null comparisons directly challenge treating coactivator deletion as mark causality. Dorighi catalytic point mutants preserve stable Mll3/4 and partners, deplete enhancer H3K4me1, but retain much enhancer RNA/Pol II; protein deletion produces larger effects (PMID28483418). Rickels genomic Trr rescue remains viable after catalytic loss or altered product specificity, with modest stress/cohesin-sensitive exceptions (PMID28967912). Rickels reuses some Dorighi mouse data, so those comparisons are not independent replication. Later extraembryonic and neural results delimit where catalysis contributes (PMID37012455,38513661), rather than making dispensability universal.

Zhang 2020 mutates both H3f3a/H3f3b alleles to H3.3K27R, sharply reducing enhancer H3K27ac while transcription/accessibility often persist (PMID32085783). Canonical H3 remains acetylatable and other acetyl marks persist; the study does not eliminate all H3K27ac or all acetylation. Dion factorial H4 lysine mutants show cumulative K5/K8/K12 effects and a distinct K16 effect (PMID15795371). That is a specific challenge to rich combinatorial instruction, with arginine-substitution chemistry and yeast scope retained. Similar H3 double-mutant transcription effects can be largely independent (PMID19087956).

Positive evidence must also be preserved. Acute DPY30/RBBP5 depletion lowers H3K4me3 before other methyl states, changes nascent RNA, and KDM5 loss delays both mark and RNA effects (PMID36859550). PIC assembly remains detectable, supporting pause-release/elongation rather than a universal initiation role. Two linked corrections are attached to the parent report and do not inflate the primary count. MLL2 catalytic knock-in and mark restoration at native genes further narrow noncatalytic alternatives (PMID38724747). Together with independent yeast Set2/Rpd3S genetic RNA endpoints (PMID16286007,16286008), these support SC2 above plausibility.

Policarpi targets individual modifications to native loci and engineered reporters with catalytic-dead controls, then tests paired modifiers (PMID38724747). The strongest paired Polycomb effect increases single-cell silencing penetrance in an engineered reporter; the authors characterize effects as at least additive and potentially synergistic. Endogenous single-mark restoration is valuable causal evidence, but cannot be borrowed to declare endogenous paired-mark necessity. Cis motifs strongly change the response. The 2025 bivalent/KAT6B report adds combination-specific recruitment plus KAT6B developmental loss (PMID39731917); it likewise needs a mark-factorial functional bridge.

Harris 2023 directly tests a widely inferred switch rather than merely reporting discordant association (PMID37945563). Haspin knockout, RNAi and inhibition leave TFIID/other reader displacement in mitosis intact, with live/fixed and antibody/nucleosome controls. H3K4me2/3 and H3T3ph tend not to coexist locally in these cells. This does not negate HP1 K9/S10 switching (PMID16222246,16222244), but shows that a peptide rule need not be the operative cellular mechanism.

The strongest explanation is context-defined mark function embedded in sequence/signaling and reader-writer feedback. The strict emergent code gate remains Γ because binding, protein-domain necessity and engineered paired output do not yet identify endogenous supra-additive mark instruction. That judgement can change with the registered factorial/rescue experiment. It does not label histone modifications epiphenomenal or use a failed universal extension to erase real narrow causality.

## HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

<!-- consensus-consistency-2026-10-09 -->
### Consensus provenance reconciliation — 9 October 2026

Case-specific Consensus discovery records were located and linked to this final edition. This supplements the review's provenance; it leaves the original assessed claim, grades and source counts intact. Provider summaries and full-text badges do not establish examination of original primary passages by this reviewer. Source access and incorporation retain the limits stated in the original methods and any dated research update.

Recorded evidence artifacts:

- `deliverables/hsef_v53_popularity_ranks_36_40_2026-10-08/histone-code/consensus/broad-ax.txt`
- `deliverables/hsef_v53_popularity_ranks_36_40_2026-10-08/histone-code/consensus/RECONCILIATION.md`
- `deliverables/hsef_v53_popularity_ranks_36_40_2026-10-08/histone-code/consensus/targeted-ax.txt`
- `deliverables/hsef_v53_popularity_ranks_36_40_2026-10-08/histone-code/consensus/usage.json`

Reported usage is preserved in the linked source-specific records; query counts and original-passage comparisons are different measures.

This provenance supplement is not a new independent or blinded adjudication. The original edition of this review carried no adversarial approval; the adversarial review of record is the one recorded in ADVERSARIAL REVIEW AND APPROVAL below. No score or confidence change is made by this reconciliation.
<!-- end-consensus-consistency -->


### Subclaim matrix and aggregation

| Subclaim | Scope | Level | Decision |
|---|---|---|---|
| SC1 Histone modifications correlate reproducibly with transcriptional states. | prespecified loci and cell states | Β | 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. |
| SC2 Individual histone marks causally contribute to specific transcriptional outputs. | mark and locus defined before outcome | Ζ | 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. |
| SC3 Histone-mark combinations causally encode outputs beyond additive individual-mark effects. | endogenous loci, reader architecture and cell state defined before outcome | Γ | 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. |

Preregistered aggregation: scope-matched. 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. Sensitivities: weakest-link Β; primary-subclaim Γ; scope-matched Γ.

### Decisive-perturbation inventory and causal tally

[37] 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.

[49] 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.

[50] 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.

[51] 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.

[58] 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.

[59] 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.

Tally: 6 discriminating contrasts. 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.

### Cap audit, precedence and Β/Γ/Δ boundary

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.

Gamma hard-rule audit: 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.

SC1 cap: “Genome-wide association and colocalization without direct perturbation cap at Β.” 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.

SC3 cap: “Mechanistic plausibility plus in vitro reconstitution or simplified cellular support caps at Γ.” 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.

SC1 field-valid definition: “
- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype
- Locus-specific disruption of looping with locus-specific effect
- Combinatorial histone-mark perturbation showing direct output dependence
- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated” Positive full-scope result: no. 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.

SC2 field-valid definition: “
- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype
- Locus-specific disruption of looping with locus-specific effect
- Combinatorial histone-mark perturbation showing direct output dependence
- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated” Positive full-scope result: yes. 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.

SC3 field-valid definition: “
- Endogenous degron of a condensate component with matched rescue, AND evidence that the specific condensate state (not generic protein loss) drives the phenotype
- Locus-specific disruption of looping with locus-specific effect
- Combinatorial histone-mark perturbation showing direct output dependence
- Critically: specificity against cell-cycle collapse, global transcriptional collapse, and replication stress must be demonstrated” Positive full-scope result: no. 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.

### Upward threshold ladder

SC1 Δ: “Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.” Satisfied: no. Association is the registered evidence type; a causal experiment tests SC2/SC3 instead of upgrading a correlative existence claim by borrowing another scope.

SC2 Δ: “Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.” Satisfied: yes. 

SC2 Ε: “Requires context-specific causality with clear scope restriction. Many enhancer, condensate, or accessibility claims belong here.” Satisfied: yes. 

SC2 Ζ: “Requires:
- Independent causal tests across loci or systems
- Specificity beyond global transcriptional collapse
- Narrowing of key alternatives” Satisfied: yes. 

SC2 Η: “Requires:
- Robust endogenous causality
- Reproducibility across loci/cell states within scope
- Strong evidence that the proposed mechanism is not a downstream correlate” Satisfied: no. 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.

SC3 Δ: “Requires at least one endogenous perturbation showing the proposed feature contributes causally to the claimed output.” Satisfied: no. 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.

Upper ladder: 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.

Independence: Convergence for SC2 spans residue/product-specific yeast genetics, mammalian catalytic knock-in/restoration and acute degron/RNA assays, addressing distinct confounders. Rickels integrates Dorighi mouse data and is partly shared; Farrelly/Zhao serotonylation papers share a programme; HP1 switch reports are independent reports of one pathway. There are 62 reports, not 62 independent positive causal lines. No independence argument upgrades SC3 absent a matching native combination test.

Yeast transcriptional fidelity genetics [49, 50, 27]: Independent genetic and RNA studies exclude purely descriptive ChIP, while the shared Set2/Rpd3S pathway is one biological family.

Mammalian mark-selective knock-in and native-locus restoration [58]: Distinguishes mark catalysis from removal of full MLL2 protein; endogenous gene loss/restoration excludes a reporter-only account.

Acute COMPASS perturbation and demethylation buffering [59]: Timing, two degron systems and KDM5 interaction narrow delayed state-change/noncatalytic alternatives; these are within one paper, not separate independent replications.

Cross-lab reader-dependent differentiation [37, 36]: Reader/rescue, species and cell-state contrasts exclude a universally passive mark signature; related TRIM33 biology is not independent factorial code confirmation.

### Falsification and pitfalls

Perturbing the proposed feature leaves the claimed output intact. H3.3K27R and MLL3/4 catalytic changes preserve much tested transcription (PMID32085783,28483418,28967912); residual marks/state boundaries prevent universal refutation. Additional downgrade: False.

Endogenous tests contradict in vitro predictions. 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. Additional downgrade: False.

Binding treated as regulation. BPTF/TAF3 affinity and structural specificity require a distinct endogenous functional endpoint.

Protein loss attributed to deposited marks. Mll3/4 and SETD1A noncatalytic functions; full NURF or KAT6B deletion does not independently manipulate mark combinations.

Metaphor reification. Code must mean a preregistered emergent interaction, not every mark-dependent recruitment.

Selective generalization. Naive ESC dispensability is not extraembryonic/neural dispensability; H3.3 is not all H3.

Provider citation substitution. Consensus broad response incorrectly attaches Ruthenburg to later catalytic-null/H3K27R claims; original records replace those pointers.

### Adversarial steelman: above, then below

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.

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.

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.

### Final score, causal direction and M/S/D

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.

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.

Momentum: Mechanistic only. 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: Stable. No named pending result is asserted to be likely to move the registered score imminently.

Divergence: Contested; no single implied-level arithmetic. These dimensions do not change level or confidence.

## PROPOSED DECISIVE EXPERIMENTS

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. Controls: 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: Combination-selective loss abolishes a reproducible interaction beyond additive effects and a paired-reading-competent rescue restores it at native loci. Falsifying: RNA effects reduce to single-mark action, writer scaffolding, charge, secondary cell-state change or promoter sequence despite loss of paired recognition.

## RESEARCH TIMELINE

| Year | Milestone | Primary source | Interpretation |
|---|---|---|---|
| 2002 | H2B-to-H3 trans-tail genetic pathway | [PMID12077605](https://pubmed.ncbi.nlm.nih.gov/12077605/) | Causal silencing/writer crosstalk, distinct from emergent information. |
| 2002 | Estrogen-linked acetylation/methylation order | [PMID12498683](https://pubmed.ncbi.nlm.nih.gov/12498683/) | Time order plus biochemical facilitation. |
| 2005 | Factorial H4 acetylation tests | [PMID15795371](https://pubmed.ncbi.nlm.nih.gov/15795371/) | Specific K16 versus cumulative other sites. |
| 2005 | Single-nucleosome gradients | [PMID16122352](https://pubmed.ncbi.nlm.nih.gov/16122352/) | Challenges many discrete deterministic states. |
| 2005 | Set2/Rpd3S transcriptional fidelity | [PMID16286007](https://pubmed.ncbi.nlm.nih.gov/16286007/) | Endogenous reader-linked cryptic initiation suppression. |
| 2005 | HP1 methyl-phospho switch | [PMID16222246](https://pubmed.ncbi.nlm.nih.gov/16222246/) | Direct chromatin binding switch; RNA scope separate. |
| 2006 | Developmental bivalent domains | [PMID16630819](https://pubmed.ncbi.nlm.nih.gov/16630819/) | Association/poising proposal. |
| 2007 | TAF3 methylation anchoring | [PMID17884155](https://pubmed.ncbi.nlm.nih.gov/17884155/) | Single-mark and DNA/acetyl cooperation. |
| 2008 | Defined H2Bub stimulates Dot1L | [PMID18449190](https://pubmed.ncbi.nlm.nih.gov/18449190/) | Biochemical crosstalk. |
| 2009 | EED feedback propagation | [PMID19767730](https://pubmed.ncbi.nlm.nih.gov/19767730/) | Reader-writer state maintenance. |
| 2010 | TRIM24 dual signature | [PMID21164480](https://pubmed.ncbi.nlm.nih.gov/21164480/) | Structural reader and contextual activation. |
| 2011 | BPTF nucleosome multivalency | [PMID21596426](https://pubmed.ncbi.nlm.nih.gov/21596426/) | Binding/localization rather than transcription necessity. |
| 2011 | TRIM33 poised activation | [PMID22196728](https://pubmed.ncbi.nlm.nih.gov/22196728/) | Reader/PHD rescue and Smad feedback. |
| 2012 | Asymmetric bivalent nucleosomes | [PMID23021224](https://pubmed.ncbi.nlm.nih.gov/23021224/) | Same nucleosome is not same histone tail. |
| 2013 | TAF3/PIC and p53 gene selection | [PMID23452851](https://pubmed.ncbi.nlm.nih.gov/23452851/) | Contextual single-mark function. |
| 2015 | Targeted p300 editing | [PMID25849900](https://pubmed.ncbi.nlm.nih.gov/25849900/) | Forced locus activation, multiple substrate limits. |
| 2017 | Stable catalytic-null versus protein loss | [PMID28483418](https://pubmed.ncbi.nlm.nih.gov/28483418/) | Separates marks from scaffolding. |
| 2017 | Trr catalytic rescue | [PMID28967912](https://pubmed.ncbi.nlm.nih.gov/28967912/) | Viability despite changed enhancer methylation. |
| 2018 | SETD1A noncatalytic domain | [PMID29474905](https://pubmed.ncbi.nlm.nih.gov/29474905/) | Protein dependence is not deposited-mark dependence. |
| 2019 | Histone serotonylation | [PMID30867594](https://pubmed.ncbi.nlm.nih.gov/30867594/) | Combinatorial recognition, ectopic mutant limits. |
| 2020 | H3.3K27R enhancer acetylation | [PMID32085783](https://pubmed.ncbi.nlm.nih.gov/32085783/) | Retained transcription and other acetylation. |
| 2023 | H3K4me3 pause-release | [PMID36859550](https://pubmed.ncbi.nlm.nih.gov/36859550/) | Acute causal RNA role; corrections attached. |
| 2023 | Haspin switch falsification | [PMID37945563](https://pubmed.ncbi.nlm.nih.gov/37945563/) | Native tests contradict peptide extrapolation. |
| 2024 | Controlled precision epigenome editing | [PMID38724747](https://pubmed.ncbi.nlm.nih.gov/38724747/) | Native single-mark effects; paired reporter penetrance. |
| 2025 | Bivalent-specific KAT6B recruitment | [PMID39731917](https://pubmed.ncbi.nlm.nih.gov/39731917/) | Protein developmental dependence needs mark-factorial bridge. |
| 2026 | NURF combinatorial recruitment and RNA | [PMID42165139](https://pubmed.ncbi.nlm.nih.gov/42165139/) | Recruitment and full-complex output are distinct tests. |

## KNOWLEDGE GAPS

Test native-locus factorial combinations with an explicit additive null rather than calling higher affinity synergy.

Separate mark identity from nucleosome geometry/asymmetry, DNA motifs and general reader avidity.

Use combination-selective reader mutants with single-mark affinity, folding and expression controls.

Compare rapid mark loss with chronic catalytic-null compensation and retained canonical histone variants.

Map MLL3/4 effects prospectively across embryonic, extraembryonic and neural states.

Distinguish initiation, polymerase pause-release, elongation and final RNA abundance.

Measure local paired occupancy quantitatively rather than overlapping bulk ChIP peaks.

Replicate NURF recruitment-to-transcription coupling with writer/reader-specific rescue rather than full complex loss alone.

Resolve KAT6B combination-specific recruitment versus its broader developmental functions.

Finish unavailable bodies/supplements and linked correction details before a complete-paper publication claim.

## METHODS AND CONSENSUS CONTRIBUTION

Consensus was used through the signed-in browser for discovery, counterevidence, research-gap and timeline suggestions, and attempted checks of specific indexed full-text passages. Provider statements about Methods/Results and any returned passages were compared with original-paper passages where available; failed retrievals, source substitutions and unverified aspects are recorded in the case reconciliation. Successful original-passage comparisons are distinguished from provider summaries and assertions of access. Provider screening counts, citation counts and meters were not used as primary counts or HSEF scores. This source log records access depth; it does not claim complete-paper or supplement review. The monthly API allowance was conserved: zero Consensus API calls in this batch.

## REVIEWER NOTES

62 primary reports examined: nine selected original partial-body checks and 53 complete abstract/status checks. Neither downloaded bodies nor provider screening counts count as examination. Dion body retrieval failed, but the full primary abstract was examined. Two Wang 2023 correction notices and the Local 2018 erratum remain attached; their details were not independently audited. No blinded calibration or complete-paper review claimed. Consensus Pro tool limit and unavailable requested texts are disclosed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

## ADVERSARIAL REVIEW AND APPROVAL

**Authoring model:** Sol 6.1. **Adversarial reviewer:** Claude Opus 5.5 (Anthropic). **Date:** 2026-10-14. This is the revised (9 October 2026) edition; the original edition was not adversarially reviewed, so this is the first adversarial review of this case.

**Scope of checks:** All 62 reference PMIDs re-fetched with the PubMed MCP tool get_article_metadata (title, first author, journal, year, DOI): 62/62 resolve to the stated record; no retraction or expression of concern. 11 load-bearing claims spot-checked against PubMed abstracts and, for PMID 38724747 (Policarpi), against the local full text in the originating batch: refs 5 (NURF, PMID 42165139), 6 (BPTF, PMID 21596426), 33 (KAT6B, PMID 39731917), 37 (TRIM33, PMID 22196728), 43 (H4 factorial, PMID 15795371), 49/50 (Set2/Rpd3S), 58 (Policarpi), 59 (PMID 36859550), plus the SC1 association sources. Scoring logic checked against the archived HSEF v5.3 framework, with particular attention to the declared scope-matched aggregation rule, the Zeta independence basis and the momentum value. Known upstream defects checked: collective-author dropping (none present), empty DOI fields (none), erratum "PMIDnot supplied" strings (none), rendering defects (six found, corrected).

**Findings and corrections**

| ID | Severity | Location | Original -> corrected | Evidence |
|---|---|---|---|---|
| HC-1 | Major | Consensus provenance reconciliation block (also consensus-addendum.md) | "The earlier adversarial approval refers to its original edition; ..." -> "...The original edition of this review carried no adversarial approval; the adversarial review of record is the one recorded in ADVERSARIAL REVIEW AND APPROVAL below." | The original edition, hsef_v53_popularity_ranks_36_40_2026-10-08/histone-code/histone-code.review.md, contains no adversarial banner and no ADVERSARIAL REVIEW AND APPROVAL section, and this slug is absent from the 2026-10-06 approved set. The 9 October revision asserted an approval that does not exist. This is a regression introduced by the revision, not an inherited error. |
| HC-2 | Major | AT A GLANCE table and the M/S/D paragraph (also scorecard extended_scoring_MSD.momentum) | Momentum "Decisive work underway" -> "Mechanistic only", with the artifact rewritten to say the named reports are completed publications and that no ongoing threshold-crossing work was verified | The artifact named only published outputs - Policarpi 2024, the 2025 bivalent/KAT6B report and the 2026 NURF report - and its own closing clause states that "no undisclosed ongoing trial or pending result is asserted". Under the lead's momentum policy, "Decisive work underway" requires work actually being run that could cross the next threshold, and a completed publication never satisfies it. Momentum modifies no letter, so no level or confidence change follows. |
| HC-3 | Major | scorecard final_score.confidence_rationale | "...9 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence..." -> rationale resting on density and reproducibility: the SC3 combination evidence is reporter-based or recruitment-only, two of the four independence lines rest on a single paper each, and contradicting results (H3K27ac loss, cumulative H4 effects, the failed TAF3 switch) are unreconciled | Lead policy: reading access is not evidence density or reproducibility and cannot set a band. Re-derived under the two-step test, the band stays **Moderate** - the review documents substantive reproducibility and evidence-quality reservations, well short of the High text's "extensive independent replication across labs, models, and assay modalities". No level or confidence change. |
| HC-4 | Minor | Research-interpretation prose, M/S/D paragraph, evidence card [5]; mirrored in the scorecard | "Zhang2020", "Harris2023", "Policarpi2024" (x1 review, x2 scorecard), "Wang2023", "Local2018", "steps3/4", "readerdomain" -> spaces and hyphen restored | Known missing-space rendering defect. |

**Rejected findings (checked, no change)**

- Scope-matched aggregation: applied correctly. SC3 is the only subclaim whose scope matches the registered claim (combinations causally encoding outputs beyond additive individual-mark effects at endogenous loci) and it sets the Γ headline; SC2 at Ζ is narrower - individual marks, not combinations - and is reported separately, exactly as the rule requires. The published sensitivities (weakest-link Β, primary-subclaim Γ, scope-matched Γ) are consistent with the matrix. Note specifically that the Ζ subclaim is **not** allowed to set the headline here, which is the correct reading.
- "Best-supported rival": correctly rendered. models_evaluated[0] is M2, is_nominal false, rank_in_tournament 1; the nominal model (M1, "Strict combinatorial instruction") is correctly at rank 3 and is not presented as the rival.
- Attribution of PMID 38724747 as an "endogenous MLL2 catalytic knock-in with targeted mark restoration" was challenged and confirmed: the Policarpi body reports ESCs "with homozygous knock-in Y2602A catalytic point mutations (CM) in the H3K4 methylase gene Mll2 (Kmt2b)", 3,102 promoter H3K4me3 peaks lost and 15,244 retained. The review's parallel description of the same paper as a dCas9-based precision epigenome-editing platform with catalytic-dead controls is also correct; both arms are in the one paper.
- "NURF writer deletions/truncations" (SC3 and the cap paragraph) reads compressed but is accurate against the source: the deleted writers are Gcn5 and Jil1, and the truncations are of the BPTF/NURF301 reader domains, as the review states explicitly in the interpretation section. No change beyond the "readerdomain" spacing fix.
- KAT6B (PMID 39731917): "combination-specific recruitment plus KAT6B developmental loss" matches the abstract, which reports that the bivalent combination recruits proteins not recruited by either mark alone, including KAT6B, and that KAT6B knockout blocks neuronal differentiation. The review correctly declines to treat this as factorial mark necessity.
- H4 factorial (PMID 15795371): the review's "cumulative K5/K8/K12 effects versus special K16 behavior" matches the abstract's two-mechanism conclusion.
- TRIM33 (PMID 22196728) and BPTF (PMID 21596426): dual-mark recognition, PHD/Bromo architecture, H3K9me3 plus H3K18ac, and mononucleosome-level H4K16ac/H3K4me3 selectivity all match the abstracts.
- PMID 36859550: acute COMPASS-subunit ablation, KDM5-dependent turnover, pause-release and elongation rather than initiation - matches the abstract.
- The compact in-text PMID lists ("PMID38724747,36859550,16286007") are house style used consistently across this batch and were left unchanged.
- Print/e-pub year differences of +/-1 at refs 16, 33, 52, 54 and 60: acceptable under the stated convention.
- Validator warning `v5.claim_form` ("entry_form is 'phenomenon'"): rejected per the standing convention. The restatement grades a causal claim - combinations read as a code that causally specifies transcriptional outputs beyond individual marks - not a bare topic.

**Residual limitations**

- 53 of 62 sources were verified at abstract/status depth. Per lead policy this bounds what was checked and is not a determinant of the confidence band.
- Two linked Wang 2023 correction notices and the Local 2018 erratum remain unexamined, as the review already states.
- scorecard provenance_header.generated_by is unchanged; authorship is recorded here as Sol 6.1 per the mandate.
- Package-level files were not edited; propagation strings are listed in the agent report.

**Approval:** Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

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58. Policarpi C, Munafò M, Tsagkris S et al. Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications. Nature genetics. 2024. [PMID 38724747](https://pubmed.ncbi.nlm.nih.gov/38724747/). DOI: 10.1038/s41588-024-01706-w. Access: full_text_partial. Study: PMID38724747.

59. Wang H, Fan Z, Shliaha PV et al. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature. 2023. [PMID 36859550](https://pubmed.ncbi.nlm.nih.gov/36859550/). DOI: 10.1038/s41586-023-05780-8. Access: full_text_partial. Study: PMID36859550.

60. Fischer JJ, Toedling J, Krueger T et al. Combinatorial effects of four histone modifications in transcription and differentiation. Genomics. 2008. [PMID 17997276](https://pubmed.ncbi.nlm.nih.gov/17997276/). DOI: 10.1016/j.ygeno.2007.08.010. Access: abstract_metadata. Study: PMID17997276.

61. 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. [PMID 34309923](https://pubmed.ncbi.nlm.nih.gov/34309923/). DOI: 10.1096/fj.202100488R. Access: abstract_metadata. Study: PMID34309923.

62. 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. [PMID 38417480](https://pubmed.ncbi.nlm.nih.gov/38417480/). DOI: 10.1016/j.bbagrm.2024.195021. Access: abstract_metadata. Study: PMID38417480.

## Source-specific evidence cards

### [1] Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability.

**Shows:** Catalytic-deficient Trr rescues fly viability; enhancer methylation changes have small transcriptional effects with stress-dependent exceptions.

**Does not show:** Does not make all marks dispensable; genomic transgene rescue, residual marks, stress phenotypes and mammalian lineage limits matter.

**Access/status:** Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Methods & Materials, 2:Main text. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [2] Readout of histone methylation by Trim24 locally restricts chromatin opening by p53.

**Shows:** Trim24 couples unmethylated H3K4 recognition to local restriction of p53 chromatin opening and gene activation.

**Does not show:** A cofactor-context mechanism is not a factorial demonstration of a multi-mark instruction code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [3] Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.

**Shows:** H3Q5ser enhances TAF3 readout and inhibits selected H3K4 erasers without equally changing all readers or writers.

**Does not show:** Binding and turnover effects do not establish endogenous combination-specific transcription beyond individual marks.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [4] Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3.

**Shows:** TAF3 PHD structure explains H3K4me3 recognition and antagonism by H3R2 methylation.

**Does not show:** A proposed methyl-methyl switch remains biochemical without locus-specific functional testing here.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [5] Combinatorial histone modifications direct ATP-dependent chromatin remodeling by NURF to promoter-proximal nucleosomes.

**Shows:** NURF recognizes triply modified H3; writer deletions/reader-domain truncation impair stable recruitment; whole Nurf301 mutants alter nucleosome positions and transcript output.

**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.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [6] Recognition of a mononucleosomal histone modification pattern by BPTF via multivalent interactions.

**Shows:** BPTF distinguishes H3K4me3/H4K16ac at nucleosome level and binding-pocket/linker mutants impair tagged BPTF localization.

**Does not show:** No endogenous transcriptional necessity test; ectopic tagged BPTF coexists with native protein and free-peptide binding lacks detectable allostery.

**Access/status:** 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. none_found. Subclaims: SC3.

### [7] Molecular determinants for recognition of serotonylated chromatin.

**Shows:** TAF3 PHD has a defined surface recognizing H3Q5ser alongside H3K4me3.

**Does not show:** Structural specificity does not demonstrate endogenous combinatorial transcriptional dependence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [8] H3K4me1 facilitates promoter-enhancer interactions and gene activation during embryonic stem cell differentiation.

**Shows:** KMT2C/D catalytic activity supports H3K4me1 and promoter-enhancer contacts at a subset of induced enhancers; KMT2B depletion worsens defects at retained sites.

**Does not show:** Contacts are not alone causal transcription; redundant writers and enhancer subclasses limit a universal activation rule.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [9] Interplay of BAF and MLL4 promotes cell type-specific enhancer activation.

**Shows:** BAF and MLL4 reciprocally support recruitment and lineage-factor-dependent enhancer activation; PBAF provides a context contrast.

**Does not show:** Protein depletion does not separate catalytic marks from coactivator scaffolds or establish combination synergy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [10] Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition.

**Shows:** MLL4 supports cell fate transition and p300 recruitment while maintenance/self-renewal can persist without it.

**Does not show:** The protein rather than its methylation activity controls p300 recruitment; no strict two-mark code follows.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [11] Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain.

**Shows:** Polycomb directly binds and inhibits CBP, linking histone acetylation to protein interaction regulation.

**Does not show:** CBP autoacetylation, protein contacts and overexpression confound attribution to a histone combination alone.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [12] MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner.

**Shows:** Eliminating MLL3/4 catalysis impairs extraembryonic lineages and gastrulation while embryonic-lineage differentiation is less dependent.

**Does not show:** Contradicts unlimited dispensability and unlimited necessity alike; lineage function does not isolate a combinatorial reader code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [13] An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells.

**Shows:** Mll4 is needed to exit naive pluripotency but its catalytic activity is dispensable; LSD1 depletion rescues Mll4-null transition.

**Does not show:** Co-regulator compensation supports a regulatory axis rather than proof that marks never act causally.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [14] A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response.

**Shows:** SETD1A FLOS/cyclin-K function controls survival and DNA damage response despite dispensable SET catalytic domain.

**Does not show:** A noncatalytic dependency cannot be counted as evidence for histone methylation or mark-combination causality.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [15] Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2.

**Shows:** EED/EZH2 structures explain allosteric stimulation by H3K27me3 and catalytic organization.

**Does not show:** Cell-free structural feedback is capped for endogenous causal output.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [16] Polycomb-dependent H3K27me1 and H3K27me2 regulate active transcription and enhancer fidelity.

**Shows:** Different H3K27 methylation states associate with distinct genomic functions and perturbations affect transcription/enhancer fidelity.

**Does not show:** Complex loss and secondary H3K36 interactions make individual-state specificity and combinatorial effects difficult to isolate.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [17] Histone methylation by PRC2 is inhibited by active chromatin marks.

**Shows:** H3K4me3/H3K36 methylation inhibit PRC2 while H3K27me3 stimulates it.

**Does not show:** Biochemical writer crosstalk establishes plausibility, not transcriptional instruction at endogenous loci.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [18] Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers.

**Shows:** Recruiting p300 catalytic core to selected promoters/enhancers activates target genes with localized H3K27ac.

**Does not show:** Ectopic recruitment and multiple p300 substrates do not isolate one residue or an endogenous combination-specific mechanism.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [19] Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation.

**Shows:** Sumoylation recruits Set3 HDAC through Cpr1 and cooperates with H2Bub/H3K4me2 to suppress cryptic transcription.

**Does not show:** A sequential crosstalk pathway does not by itself define emergent information in simultaneous mark combinations.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [20] Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation.

**Shows:** Site-specific H2B ubiquitination directly stimulates intranucleosomal Dot1L H3K79 methylation.

**Does not show:** Purified writer activity is not endogenous transcriptional causality.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [21] Structural Basis for Recognition of Ubiquitylated Nucleosome by Dot1L Methyltransferase.

**Shows:** Dot1L contacts ubiquitin and the acidic patch in a methylation-ready configuration.

**Does not show:** Structural activation does not establish a combinatorial gene-output code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [22] Cotranscriptional histone H2B monoubiquitylation is tightly coupled with RNA polymerase II elongation rate.

**Shows:** H2Bub tracks polymerase advance and elongation rate more closely than slower methyl marks.

**Does not show:** A cotranscriptional readout is not an upstream instruction; pausing associations do not establish primacy.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

### [23] Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome.

**Shows:** COMPASS bridges ubiquitin and nucleosome contacts to stimulate H3K4 methylation across histone tails.

**Does not show:** Reconstituted crosstalk does not specify endogenous transcriptional output beyond constituent effects.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [24] Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation.

**Shows:** H4K16ac and H2Bub cooperate in regulating Dot1 H3K79 methylation and silencing.

**Does not show:** Writer stimulation and epigenetic maintenance are not a general deterministic code; full report access remains abstract-only here.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [25] Nucleosome contact triggers conformational changes of Rpd3S driving high-affinity H3K36me nucleosome engagement.

**Shows:** Nucleosome contacts allosterically activate Eaf3 through Rco1; interface mutations preserve complex integrity but impair function.

**Does not show:** Multivalent chromatin engagement includes unmodified structural contacts; not necessarily a specific mark-combination instruction.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [26] Global mapping of the regulatory interactions of histone residues.

**Shows:** Histone-residue perturbations map regulatory associations with methylases and deacetylases.

**Does not show:** Mutations alter residue chemistry and expression similarity does not by itself establish epistasis or specific combinatorial reading.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [27] Unique and Shared Roles for Histone H3K36 Methylation States in Transcription Regulation Functions.

**Shows:** Engineered methylation states show shared cryptic-transcription suppression and a distinct H3K36me3-associated Bur1/FACT function.

**Does not show:** Redundancy among states limits a one-state/one-output vocabulary; stress and yeast scope remain bounded.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [28] Histone Modifications Regulate Chromatin Compartmentalization by Contributing to a Phase Separation Mechanism.

**Shows:** Reader/writer/scaffold multivalency promotes dense, DNase-resistant H3K9-methylated droplets excluding TFIIB.

**Does not show:** In vitro droplets and exclusion do not establish endogenous phase separation or transcriptional instruction.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [29] Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B.

**Shows:** DNMT3B recognizes H3K36me3 through a defined aromatic/water pocket; a disease mutation disrupts affinity.

**Does not show:** Structural model is not a direct endogenous transcriptional or combinatorial causal test.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

### [30] Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation.

**Shows:** TAF3/TAF5 and other H3K4 readers still leave mitotic chromosomes when H3T3ph is absent; adjacent H3K4me2/3 suppresses H3T3 phosphorylation.

**Does not show:** Refutes this proposed cellular switch in tested cells, not all methyl-phospho switching; CIDOP is an isolated-chromatin assay.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [31] A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

**Shows:** Developmental promoters carry regional H3K4/H3K27 bivalency and low expression with sequence associations.

**Does not show:** Regional coexistence and proposed poising are not factorial endogenous causal instruction.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [32] Asymmetrically modified nucleosomes.

**Shows:** Bivalent marks occupy opposite H3 tails; asymmetric placement permits PRC2 activity unlike symmetric placement.

**Does not show:** Nucleosomal asymmetry changes biochemistry; functional poising requires separate perturbation evidence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [33] Nucleosomal asymmetry shapes histone mark binding and promotes poising at bivalent domains.

**Shows:** Asymmetric bivalent nucleosomes recruit KAT6B beyond either mark alone; KAT6B loss blocks neuronal differentiation.

**Does not show:** Reader-complex loss is not factorial mark removal with rescue; developmental failure need not prove the combination itself specifies output.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [34] Single-molecule decoding of combinatorially modified nucleosomes.

**Shows:** Directly detects co-modified nucleosomes and state-specific effects of enzyme perturbation.

**Does not show:** Technology and state abundance do not establish causal combinations beyond additive effects.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [35] TRIM24 links a non-canonical histone signature to breast cancer.

**Shows:** TRIM24 tandem reader recognizes H3K4me0/H3K23ac and supports estrogen-dependent gene activation.

**Does not show:** Patient survival is associative; reader/protein effects do not independently manipulate both endogenous marks.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [36] H3K18ac Primes Mesendodermal Differentiation upon Nodal Signaling.

**Shows:** H3K18ac and TRIM33 accessibility prime nodal responses in embryoid bodies with a contrasting ESC context.

**Does not show:** p300/HDAC1 regulate multiple substrates; the specific two-mark interaction is not independently factorially tested.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [37] A poised chromatin platform for TGF-β access to master regulators.

**Shows:** TRIM33 loss selectively blocks mesendodermal genes; wild-type but not PHD-deleted rescue restores response; dual-mark binding coexists with Smad-dependent feedback.

**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.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [38] Multivalent engagement of TFIID to nucleosomes.

**Shows:** H3K4me3, acetylation and TATA DNA synergize in TFIID binding, and TAF3 PHD supports rapid gene induction.

**Does not show:** Binding synergy with DNA is not factorial endogenous histone-only output dependence.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [39] Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4.

**Shows:** H3K4me3 loss reduces TFIID/promoter activity in subsets; R2 methylation antagonizes and acetylation potentiates binding.

**Does not show:** Selective single-mark effects and transient coactivation do not establish a general multi-mark code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [40] H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation.

**Shows:** H3K4me3-TAF3 supports PIC assembly and selective p53 activation, cooperatively with TATA elements.

**Does not show:** DNA/mark cooperation and cellular context do not demonstrate histone-combination causality.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [41] Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation.

**Shows:** H3S10 phosphorylation ejects HP1 despite persistent H3K9me3; Aurora-B inhibition retains HP1 in mitosis.

**Does not show:** HP1 relocation is a protein/chromatin endpoint, not direct combination-specific transcriptional output.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [42] Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin.

**Shows:** H3K9me3S10ph marks mitotic heterochromatin and blocked phosphorylation prevents HP1 release.

**Does not show:** Supports a reader-binding switch but not the registered transcription code; mitotic kinase pleiotropy needs controls.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [43] Genomic characterization reveals a simple histone H4 acetylation code.

**Shows:** All H4 lysine-mutant combinations separate a specific K16 effect from cumulative K5/K8/K12 transcription effects.

**Does not show:** Arginine substitutes charge/nonmodifiable chemistry, not acetylation alone; findings are yeast H4 scope rather than universal refutation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [44] Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation.

**Shows:** Stable catalytic-null Mll3/4 proteins retain enhancer transcription despite mark loss; protein deletion suppresses polymerase/eRNA and nearby genes.

**Does not show:** Residual H3K4me1 and naive ESC state constrain dispensability; protein dependence is not mark dependence.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [45] Histone H3 lysine 4 monomethylation modulates long-range chromatin interactions at enhancers.

**Shows:** MLL3/4-dependent H3K4me1 contributes to cohesin recruitment, contacts and differentiation-linked gene activation.

**Does not show:** Mark/protein perturbation and contacts need specificity; linked erratum attached and its detailed correction was not independently examined.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. ErratumIn: PMID29497152. Subclaims: SC2, SC3.

### [46] Histone H3K27 acetylation is dispensable for enhancer activity in mouse embryonic stem cells.

**Shows:** Mutating both H3.3 genes sharply reduces enhancer H3K27ac while many transcripts/accessibility features persist.

**Does not show:** Canonical H3 remains modifiable and other acetyl marks remain; no total-H3K27ac or all-context dispensability follows.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [47] Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation during embryonic stem cell differentiation.

**Shows:** Many enhancers lose changing H3K4me1/H3K27ac without preventing activation of nearby genes; stable and dynamic sites differ.

**Does not show:** Nearest-gene assignment and alternative activating pathways constrain inference; this is not proof all enhancer marks are inert.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [48] Eaf3 chromodomain interaction with methylated H3-K36 links histone deacetylation to Pol II elongation.

**Shows:** Eaf3 recognition of methylated H3K36 supports coding-region deacetylation and suppresses internal initiation.

**Does not show:** A transcription-coupled reader pathway is not necessarily simultaneous combinatorial instruction.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [49] Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription.

**Shows:** Set2 acts upstream of reader-dependent Rpd3S deacetylation to suppress intragenic transcripts.

**Does not show:** Establishes a causal mark/reader pathway at coding regions, not a rich deterministic multi-mark code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [50] Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex.

**Shows:** Eaf3 recruits Rpd3S to Set2-methylated coding chromatin and mutations affect transcriptional regulation/Bur1 dependence.

**Does not show:** Shares yeast pathway biology with other reports; distinct laboratory work is not proof of universal combinatorial encoding.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [51] Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast.

**Shows:** H2B ubiquitination precedes H3K4 methylation and H2B K123R perturbs telomeric silencing.

**Does not show:** Residue mutations and Rad6 pleiotropy constrain specificity; ordered writer crosstalk is distinct from emergent output encoding.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [52] Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription.

**Shows:** Regulated H2B deubiquitination supports GAL10 activation and coupled H3K4 methylation.

**Does not show:** SAGA also acetylates and scaffolds transcription; multiple functions prevent code-only attribution.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [53] Role of the polycomb protein EED in the propagation of repressive histone marks.

**Shows:** EED recognizes repressive methyl-lysines to stimulate PRC2; binding mutants impair methylation/development.

**Does not show:** Feedback propagation does not alone specify combinatorial transcription outputs.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [54] Genetic and genomewide analysis of simultaneous mutations in acetylated and methylated lysine residues in histone H3 in Saccharomyces cerevisiae.

**Shows:** Acetylated/methylated residue mutants show growth interaction but largely independent gene-expression effects and different Sir4 binding.

**Does not show:** Interdependence is phenotype-specific; residue replacements do not selectively erase one chemical mark.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [55] Crosstalk between CARM1 methylation and CBP acetylation on histone H3.

**Shows:** Acetylation precedes CARM1 methylation and facilitates binding/activity at estrogen-responsive chromatin.

**Does not show:** Exogenous CBP sufficiency and ordered deposition do not prove endogenous supra-additive combination output.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [56] Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3.

**Shows:** H3K4me3Q5ser occurs in vivo, enhances TFIID interaction, and nonserotonylatable ectopic H3 alters differentiation/transcription.

**Does not show:** Ectopic mutant and writer multiple substrates cap inference to endogenous combinatorial necessity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [57] Single-nucleosome mapping of histone modifications in S. cerevisiae.

**Shows:** Twelve modifications form broad co-occurring gradients rather than many discrete deterministic states.

**Does not show:** Observational mapping cannot disprove specific causal combinations elsewhere; continuous patterns may remain functional.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [58] Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.

**Shows:** MLL2 catalytic loss and targeted mark restoration support H3K4me3-dependent endogenous genes; paired Polycomb mark targeting increases reporter silencing penetrance.

**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.

**Access/status:** 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. none_found. Subclaims: SC2, SC3.

### [59] H3K4me3 regulates RNA polymerase II promoter-proximal pause-release.

**Shows:** Two acute loss systems and delayed demethylation connect H3K4me3 to transcriptional pause-release/elongation while PIC assembly persists.

**Does not show:** Shared SET1/COMPASS functions and proliferation effects limit perfect specificity; linked corrections remain attached, not separate primary counts.

**Access/status:** 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. ErratumIn: PMID36941349; ErratumIn: PMID37907651. Subclaims: SC2, SC3.

### [60] Combinatorial effects of four histone modifications in transcription and differentiation.

**Shows:** Expression associations depend on mark combinations; many mark changes remain uncoupled from transcript changes.

**Does not show:** This is observational combinatorial association rather than intervention-driven code validation.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

### [61] Histone H3K4me1 and H3K27ac play roles in nucleosome eviction and eRNA transcription, respectively, at enhancers.

**Shows:** H3K4me1/MLL3/4 and p300/H3K27ac perturbations affect eviction and eRNA asymmetrically at beta-globin enhancers.

**Does not show:** Enzyme-domain lesions affect multiple outputs/substrates; differing individual roles do not establish supra-additivity.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

### [62] Histone H3K4ac, as a marker of active transcription start sites and enhancers, plays roles in histone eviction and RNA transcription.

**Shows:** H3K4ac relates to eviction/transcription and can overlap redundantly with H3K27ac in eRNA regulation.

**Does not show:** p300 and MLL3/4 affect many marks; interdependence and redundancy are distinct from a strict code.

**Access/status:** Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.