H3K4me3 oscillates around the clock and MLL1 is what lets it - a cell state of KMT2A biology this project has never once mentioned
also called MLL1 in the circadian clock · rhythmic H3K4me3
The chemical tag KMT2A writes on DNA packaging rises and falls on a 24-hour rhythm at clock-controlled genes, and without KMT2A the rhythm fails. Nothing in this corpus's 2,396 pre-existing entries had noticed that the gene it is named after is part of the body clock.
The same thing, for a scientist
H3K4 trimethylation at circadian promoters is rhythmic and follows the same profile as the previously described rhythmic H3 acetylation; MLL1 is essential for circadian transcription and for cyclic H3K4 trimethylation, sits in a complex with CLOCK-BMAL1, and contributes to CLOCK-BMAL1's rhythmic recruitment to circadian promoters and to H3 acetylation; MLL1 fails to interact with the CLOCK-delta19 mutant, which is offered as the explanation for that mutation's dominant-negative phenotype [E1]. Recorded here as a CELL STATE because it is a time-varying chromatin state of the same writer this project studies, and because it makes a prediction about menin inhibition that nobody has tested: if MLL1-dependent H3K4me3 is rhythmic, then occupancy and pharmacodynamic readouts taken at a single clock time are sampling a moving target.
What was shown
Katada and Sassone-Corsi 1:
- H3K4me3 at circadian promoters is rhythmic, with the same profile as circadian H3 acetylation.
- MLL1 is essential for circadian transcription and for cyclic H3K4me3.
- MLL1 is in a complex with CLOCK-BMAL1 and contributes to its rhythmic promoter recruitment and to H3 acetylation.
- MLL1 does not interact with CLOCK-delta19, the classic dominant-negative clock mutant.
Their conclusion is that MLL1-deposited H3K4me3 establishes a permissive chromatin state for circadian transcription.
Why a leukaemia graph should care
Three reasons, in increasing order of how much they should change behaviour.
- Completeness. UniProt and HPA both list 'Biological rhythms' among KMT2A's biological processes. This corpus, which had 2,396 entries before this beat and exhaustive coverage of obscure fusion partners, contains the word 'circadian' in nine entries and in none of them about KMT2A.
- Sampling. Every ChIP, CUT&RUN and occupancy measurement in this project is taken at one unrecorded time of day. If MLL1-dependent H3K4me3 is rhythmic at a subset of promoters, between-experiment variance at those promoters has a component nobody is controlling and nobody is reporting.
- Pharmacodynamics. Menin-inhibitor trials measure target engagement by menin and MLL1 eviction from chromatin. A rhythmic component in the baseline makes a single-timepoint pharmacodynamic sample less informative than it looks, and the direction of the error depends on sampling time relative to the patient's clock.
None of these is a demonstrated problem. All three are cheap to check and none has been checked.
The limits, stated plainly
This is one 2010 paper in mouse and cultured cells, on wild-type MLL1, with no leukaemia and no fusion anywhere in it. The mechanism could be entirely irrelevant to a leukaemic blast, whose clock may be disrupted for unrelated reasons. What it is NOT is absent from the literature, which is what this graph implicitly asserted by never mentioning it.
| state class | time-varying chromatin state |
|---|---|
| period | circadian, approximately 24 h |
| mark | H3K4me3 |
| requirement | MLL1 essential for the oscillation (PMID 21113167) |
| partner complex | CLOCK-BMAL1; no interaction with CLOCK-delta19 |
| shown for fusion | NO - nobody has looked in any KMT2A fusion, and no circadian measurement exists in any leukaemic cell in this corpus. |
| corpus status before this cycle | PMID 21113167 had ZERO mentions - as a citation or in prose - across the 2,396 node files outside this beat's folder, measured 2026-09-23 and persisted in analyses/q127-the-pi-dimensions-at-the-centre/results.json. The token 'circadian' appears in 9 entries, none of them about KMT2A. |
| absence class | never-measured |
| absence class note | The absence recorded in this entry is not the circadian biology itself, which is published, but the leukaemic arm of it: no circadian or time-of-day-resolved measurement of H3K4me3, MLL1 occupancy or menin occupancy exists in any KMT2A-rearranged system. GEO was queried on 2026-09-23 for a menin-inhibitor dataset with an H3K4 readout and returned 0 series (querytranslation: ((menin[All Fields] AND inhibitor[All Fields]) OR ("revumenib"[All Fields] OR revumenib[All Fields]) OR VTP-50469[All Fields]) AND H3K4[All Fields]), so no deposited data could be reanalysed for a diurnal component either. This is wet work, hence never-measured rather than measured-not-analysed. |
- If the target's chromatin state oscillates, a once-daily drug schedule interacts with the biology in a way that dosing studies designed around plasma half-life will not detect, and a trough sample can under- or over-report engagement depending on clock phase.
- Is MLL1-dependent H3K4me3 rhythmic in a haematopoietic cell, and is it rhythmic at the HOXA cluster? A six-timepoint H3K4me3 CUT&RUN over 24 h in a synchronised HSPC culture would answer it and costs one experiment.
- Does time of sampling change a menin-inhibitor pharmacodynamic readout? Trial correlative samples are drawn at clinic convenience. If the answer is yes even weakly, every occupancy comparison across patients has an uncontrolled covariate.
- Are KMT2A-rearranged blasts arrhythmic? cell-state-unsynchronisable-cell-cycle already records that five KMT2A-rearranged lines refuse chemical cell-cycle synchronisation. Whether the circadian clock is also broken in them is unasked and would be visible in a Bmal1-luciferase reporter in a week.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Trimethylation of histone H3 lysine 4 is rhythmic at circadian promoters and follows the same profile as circadian H3 acetylation; MLL1 is essential for circadian transcription and for cyclic H3K4 trimethylation, is in a complex with CLOCK-BMAL1, contributes to CLOCK-BMAL1's rhythmic recruitment to circadian promoters and to H3 acetylation, and fails to interact with CLOCK-delta19.
The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. · Katada S, Sassone-Corsi P · Nat Struct Mol Biol 2010What this evidence cannot show
Mouse and cultured cells; abstract read, full text not opened, so the promoter set, the amplitude of the H3K4me3 oscillation and the number of timepoints are not recorded here and must not be inferred. Single paper, no independent replication identified in this beat. Confidence is set to moderate for that reason, not because the paper is weak. No leukaemia, no fusion, no haematopoietic cell.
Evidence that argues against this (1)
- The same laboratory-independent result that bounds MLL1's H3K4me3 requirement to under 5% of marked promoters cuts against a broad reading of this one: if MLL1 is dispensable for the mark at 95% of promoters, a rhythm that depends on MLL1 is a rhythm at a small, specific promoter set, and nothing establishes that HOXA or any leukaemia-relevant locus is in it. Wang P et al. 2009
- ← regulatesKMT2A / MLL1 — the gene that breaks
MLL1 is essential for cyclic H3K4me3 at circadian promoters (PMID 21113167)
the oscillating mark
the other time-domain anomaly of KMT2A-rearranged cells recorded in this graph
the restricted MLL1 H3K4me3 requirement, of which the circadian promoters are one named subset