At the Hox cluster, menin is required for most of the H3K4 methylation and MLL1 is required for only a subset - the cofactor has a bigger chromatin footprint than the enzyme
also called menin exceeds MLL1 at Hox · menin-dependent H3K4 methylation
You would expect the enzyme to matter more than the helper protein it docks onto. At the Hox genes, the opposite is measured: removing the helper, menin, wipes out nearly all of the chemical mark, while removing the enzyme MLL1 only affects some of it.
The same thing, for a scientist
In the same Mll1-null mouse embryonic fibroblast system in which Mll1 proved necessary for H3K4me3 at under 5% of marked promoters, the authors report that Mll1 is required for methylation of only a SUBSET of Hox genes, whereas menin - a component of both the Mll1 and Mll2 complexes - is required for the OVERWHELMING MAJORITY of H3K4 methylation at Hox loci [E1]. The natural reading is that menin's chromatin requirement at these loci is carried by more than one COMPASS-like complex, MLL2 included, and is therefore broader than MLL1's. This is the direct answer to the standing instruction that menin's chromatin role must not be assumed to be KMT2A's, and it is the epigenetics entry gene-men1 has never had.
The comparison, as the authors state it
'Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs.' 1
Three separate facts sit in that sentence and only the first is usually quoted: MLL1 partial, menin near-total, MLL3/MLL4/Set1 negligible. The third is what makes the second interesting, because it rules out the obvious explanation that everything else is covering for MLL1.
What it implies for the drug
A menin inhibitor disrupts the menin-MLL1 contact. If menin's Hox requirement is carried through MLL2 as well as MLL1, then the drug's effect on Hox chromatin is not simply 'the MLL1 arm switched off' - it depends on whether the same inhibitor also displaces menin from MLL2, which shares the menin-binding motif.
This graph should be careful here: the Wang result is a genetic requirement in fibroblasts, not a drug experiment, and it does not measure MLL2's contribution directly. What it establishes is that menin's footprint at Hox is larger than MLL1's, which is a constraint on any account that treats menin purely as an MLL1 adaptor.
Not the same claim as the CDK-inhibitor axis
mechanism-menin-mll-h3k4-methylation-at-cdkn1b-and-cdkn2c records menin-directed H3K4 methylation at CDKN1B and CDKN2C in endocrine cells. This entry records menin-directed H3K4 methylation at Hox loci in fibroblasts. Same activity, different address lists, opposite cell-state outputs - proliferative restraint at one, developmental identity at the other. Keeping them as separate entries is the point; the interesting object is the pair.
| epigenetic readout | MENIN IS NOT A WRITER, ERASER OR READER OF ANY HISTONE MARK. It carries no SET, JmjC, HAT, HDAC, bromo, chromo, Tudor, PHD or CXXC module. Its epigenetic role is as the docking adaptor that puts an H3K4 methyltransferase on a locus, and the measurable consequence is that menin loss removes H3K4 methylation at addresses where MLL1 loss does not: the overwhelming majority of H3K4 methylation at Hox loci is menin-dependent while only a subset is MLL1-dependent, and MLL3/MLL4 and Set1 complexes contribute little to nothing there [E1]. In endocrine cells the same adaptor directs H3K4 methylation onto CDKN1B and CDKN2C instead (PMIDs 15640349, 16195383; see mechanism-menin-mll-h3k4-methylation-at-cdkn1b-and-cdkn2c). |
|---|---|
| inference not source claim | that MLL2/KMT2B carries the menin-dependent residual at Hox is the obvious reading of 'a component of the Mll1 AND Mll2 complexes', but the paper as abstracted does not test MLL2 loss, so this graph records it as an inference |
| why it matters for the drug | a menin inhibitor targets the menin-MLL interface, and the menin-binding motif is shared between KMT2A and KMT2B; if menin's Hox footprint runs through both, the drug's chromatin effect is broader than 'MLL1 off' |
comparison
{
"locus_set": "Hox loci",
"mll1_requirement": "a SUBSET of Hox genes",
"menin_requirement": "the OVERWHELMING MAJORITY of H3K4 methylation",
"mll3_mll4_set1_requirement": "little to no effect",
"system": "Mll1-null mouse embryonic fibroblasts, PMID 19703992"
}- If menin's chromatin requirement is broader than MLL1's, then menin inhibition has effects the fusion-centric model does not predict, and off-fusion chromatin changes would be read as 'differentiation' rather than as off-target activity.
- Sharing the menin-binding motif with KMT2B means the drug cannot be selective for the fusion at the level of the interface, only at the level of which cell depends on the output.
- Does KMT2B (MLL2) carry the menin-dependent residual at Hox, and is it displaced by revumenib? The menin-binding motif is shared, and no entry in this graph measures menin inhibitor occupancy loss at KMT2B targets.
- Is the same asymmetry true in a haematopoietic cell? Everything here is fibroblast. If menin's footprint exceeds MLL1's in an HSPC too, then menin inhibition is a broader chromatin intervention than the fusion-centric account implies.
- Does the asymmetry survive in a fusion-bearing cell, where the fusion itself binds menin with the same motifs and is present at high copy? The competition between fusion, wild-type KMT2A and KMT2B for a limiting menin pool has never been measured.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Although Mll1 is required for the methylation of only a subset of Hox genes, menin - a component of the Mll1 and Mll2 complexes - is required for the overwhelming majority of H3K4 methylation at Hox loci, while loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on H3K4 methylation of Hox loci or their expression levels in these mouse embryonic fibroblasts.
Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. · Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, Ge K, Krumlauf R, Shilatifard A · Mol Cell Biol 2009What this evidence cannot show
Mouse embryonic fibroblasts, not a haematopoietic or endocrine cell and no fusion present. 'Overwhelming majority' is the authors' wording and no percentage appears in the abstract; abstract read, full text not opened, so the menin depletion method (knockout versus knockdown) and its efficiency are not recorded here and would change how strong the claim is. The inference that MLL2 carries the residual requirement is stated in this entry as an inference, not as a source claim. NOT CITED anywhere in this corpus before 2026-09-23.
Evidence that argues against this (1)
- A haematopoietic study of the same question reaches a weaker conclusion: the Mll-dependent HSC network contains BOTH menin-dependent and menin-independent target genes, which is not the near-total menin dependence this fibroblast measurement reports at Hox. Either the tissue differs or the locus set differs, and neither study tests the other's system. Artinger EL et al. 2013
menin is required for the overwhelming majority of H3K4 methylation at Hox loci (PMID 19703992)
same paper, same system, the two halves of the asymmetry
the locus set at which the asymmetry was measured
the same adaptor activity at a different address list with the opposite cell-state output
the haematopoietic limb of the hypothesis