Concept
Histone Modifications
3 studiesEvidence last moved Sep 20, 2026
Histone modifications are chemical groups added to histone proteins that alter how the DNA wrapped around them is read. Beyond the familiar acetylation and methylation, the studies here concern marks derived from metabolites — lactate and monoamines — which places chromatin state downstream of cellular metabolism.
If a histone mark is built from a metabolic intermediate, then metabolism is not merely a consequence of gene expression but an input to it. That reframes metabolic changes in cancer and in the brain as potentially regulatory rather than incidental — and each study here supplies a specific instance.
Studies
3
Findings
4
4 supporting · 0 challenging · 0 qualifying citations
Open tensions
1
Latest change
Concept page published
Histone Modifications
Currently
What we know
- The chain runs mutation to metabolism to chromatin mark to phenotype, each step measured.
- The genotype-specific response is what elevates this above a correlation with the mark.
- The rescue experiment places SP100A on the path rather than beside it.
- Two monoamine marks at the same residue have opposite effects on the same downstream complex.
Largest unresolved question
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
Common misconceptions
Histone marks are written and erased by dedicated, separate enzymes.
Transglutaminase 2 functions as writer, eraser and exchanger for histone monoaminylation, so the same enzyme can add, remove and swap the mark depending on conditions.
Elevated lactate in tumours is just a by-product of altered metabolism.
Lactate supplies the group for histone lactylation. In KRAS-mutant colorectal cancer the resulting H3K9la was higher, predicted worse survival, and inhibiting it reduced growth in patient-derived xenografts — making the by-product a regulatory input.
Related
Claim ledger
What the evidence shows
Drawn from 3 studies in this library. Mix labels say which citation roles are present; they are not a strength score. Supports means evidence for a finding; Challenges means evidence against a stated position; Qualifies marks scope.
The chain runs mutation to metabolism to chromatin mark to phenotype, each step measured.
A driver mutation raised a lactate-derived histone mark, and the mark predicted outcome. KRAS-mutant colorectal tumours showed higher H3K9 lactylation, high H3K9la predicted worse survival, and mutant KRAS induced GRAMD1A to promote cholesterol metabolism, growth and metastasis.
The genotype-specific response is what elevates this above a correlation with the mark.
Blocking the mark reduced tumour growth in patient-derived models. Inhibiting H3K9 lactylation or GRAMD1A cut growth in patient-derived xenografts, with a larger effect in KRAS-mutant tumours.
The rescue experiment places SP100A on the path rather than beside it.
Lactylation acts through downstream enzymes, not only through general chromatin state. In high-risk ocular melanoma, lactylation-linked upregulation of ALKBH3 accompanied m1A hypomethylation; demethylating SP100A impaired PML body formation, and silencing ALKBH3 had therapeutic efficacy that SP100A depletion reversed.
Two monoamine marks at the same residue have opposite effects on the same downstream complex.
Monoaminylation marks are dynamic and regionally specific. Transglutaminase 2 acts as eraser and exchanger as well as writer, and H3Q5 histaminylation is diurnally rhythmic in brain — enriched in the histaminergic tuberomammillary nucleus, the only HDC-positive region — where, unlike H3Q5 serotonylation, it inhibits WDR5 binding and so H3K4 methyltransferase activity.
Debates
Tensions and limits
Some items are genuine disagreements on the same question. Others mark different assays, populations, or outcomes.
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
- How does mutant KRAS rewrite CRC chromatin with lactate?
- Can one enzyme put histamine on histones and take it off?
Study Role Design N Population Outcome How does mutant KRAS rewrite CRC chromatin with lactate? Supports Animal / in-vitroKRAS-mutant vs wild-type CRC tissues, cell lines, ChIP/RNA-seq, and PDX mice testing H3K9la–GRAMD1A–cholesterol signaling N=167 · Immunofluorescence on 130 CRC and 37 normal colon tissues; plus cell lines, TCGA, and KRAS-mutant/wild-type PDX models Human colorectal tumors and matched normals, CRC cell lines, TCGA transcriptomes, and CRC patient-derived xenograft mice H3K9la/lactylation levels, GRAMD1A expression, cholesterol metabolism, proliferation/migration, survival, and PDX tumor growth Can one enzyme put histamine on histones and take it off? Supports Animal / in-vitroBiochemical, genomic, and mouse work showing TG2 writes/erases H3Q5 monoaminylations, including rhythmic H3Q5his in TMN N=25 · Multiple assays; example in vivo n = 12 zolpidem vs 13 vehicle mice plus TMN-focused molecular time courses Biochemical systems, mouse brain (especially histaminergic TMN), and circadian/behavioral assays H3Q5ser/dop/his dynamics, WDR5/H3K4 methylation antagonism, circadian gene expression and locomotor rhythmicity
PaperFren reads this as a limit on how far one study travels — different assays, populations, or outcomes — not a forced fight between papers.
Timeline
How understanding moved
Study years are when the paper was published. Evidence edits are dated changes to this page's claims. Explanations are when PaperFren added a Discovery — not a claim that the science happened that day.
2026
Concept page published
Histone Modifications
Change log
What changed
Dated edits to this page's evidence: studies added or removed from a claim, claims added or withdrawn, and new explanations tagged here. Rewordings are not listed.
- Concept page published
Papers
3 studies in this library bear on Histone Modifications, ordered by citations.
- How does lactylation-driven ALKBH3 weaken tumor suppressors?
Histone lactylation boosts ALKBH3, which removes m1A from SP100A and diminishes PML nuclear condensates, accelerating ocular melanoma progression.
- How does mutant KRAS rewrite CRC chromatin with lactate?
In KRAS-mutant colorectal cancer, extra lactate boosts H3K9 lactylation, which opens chromatin at GRAMD1A and fuels cholesterol-driven growth; blocking H3K9la or GRAMD1A shrinks PDX tumors.
- Can one enzyme put histamine on histones and take it off?
Transglutaminase 2 not only installs serotonin/dopamine on histone H3Q5 but also erases and swaps those marks; histaminylation (H3Q5his) rises and falls over the day, blocks WDR5, and helps set neural circadian gene expression and behavior.
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Questions
What is still open
These marks are studied in systems that answer different questions. The cancer work links lactylation to outcome and to treatment response in patient-derived models, while the monoaminylation work establishes enzymology and rhythmicity in brain without an outcome — so the strength of evidence for the mark mattering differs by field rather than by mark.
Ask PaperFren about Histone Modifications
Study this conceptflashcards and short-answer questions
What distinguishes a histone mark that matters from one that merely correlates with a phenotype?
A manipulation with a specific, predicted consequence. High H3K9 lactylation correlating with worse colorectal survival is a correlation; inhibiting H3K9la or GRAMD1A reducing patient-derived xenograft growth more in KRAS-mutant tumours is a test, because the genotype-dependence was predicted by the proposed mechanism and could have failed.
Why is it significant that two monoamine marks at the same residue behave differently?
Because it rules out a nonspecific steric account. H3Q5 histaminylation inhibits WDR5 binding and therefore H3K4 methyltransferase activity, while H3Q5 serotonylation does not — at the same position. If the effect came simply from occupying the residue, both would act alike, so the identity of the attached monoamine is doing the work.
What does the regional enrichment of H3Q5his in the tuberomammillary nucleus add?
It ties the mark to local substrate availability. The tuberomammillary nucleus is the only HDC-positive region — the only place making histamine — and it is where the histaminylation mark is enriched and diurnally rhythmic. Coupling the mark's distribution to where its substrate is produced is what supports reading it as metabolically driven rather than as a region-specific enzyme difference.