MechanismstrongQ59-marks2

H3K9me3 - measured in KMT2A::AFF1 cells, in a supplementary figure, and it rises GENERALLY where H3K27ac falls SPECIFICALLY in the same experiment

also called H3K9me3 · H3K9 trimethylation · histone H3 lysine 9 trimethylation · H3K9Me3 · trimethyl-H3K9

H3K9me3 is the tag that locks a stretch of DNA into silent, tightly packed chromatin. In KMT2A-fusion leukaemia it is the brake: the enzymes that write it push down the very genes the fusion needs, and leukaemia stem cells carry less of it than normal blood stem cells. When a DOT1L inhibitor is given it goes up - but everywhere, not just at the genes the drug is aimed at.

The same thing, for a scientist

H3K9me3 is the constitutive-heterochromatin mark written by SUV39H1/H2 and SETDB1, read by HP1 proteins, and erased by the KDM4/JMJD2 demethylases. **In KMT2A-rearranged leukaemia it behaves as a tumour suppressor at the fusion's own target genes.** SETDB1 binds the PAF1 complex - the complex this graph already holds as required for fusion localisation - and the PAF1c-SETDB1 interaction deposits promoter H3K9me3 at *Meis1* and *Hoxa9*, repressing them in MLL-AF9-transformed AML cells; stabilising that interaction with a CDC73_3YF mutant, or over-expressing SETDB1, raises the mark and lowers the transcripts, and in human AML higher SETDB1 tracks with lower HOXA9 and MEIS1 [E1, E2]. Independently, SUV39H1 is down-regulated across leukaemias including MLL-r AML, and both Suv39h1 expression and **genomic H3K9me3 occupancy are decreased in leukaemia stem cells from MLL-r models relative to their normal counterparts** [E3]. **The measurement in the index fusion exists and is easy to miss.** In human SEM cells (KMT2A::AFF1) a DOT1L inhibitor produces a modest increase in H3K9me3 that the authors describe as *general* - it occurs at H3K79me2/3-marked enhancers, at non-KEE enhancers and at a non-enhancer control region alike - and they conclude explicitly that it does **not** explain the KEE-specific changes [E4]. That result is in Supplementary Fig. 4b-e of a paper whose abstract names neither H3K9me3 nor SEM, and it is the cleanest available contrast to H3K27ac, which falls at KEEs only in the very same experiment.

Go deeper

The same drug, the same cells, two marks, two geometries

PMID 31243293 ran H3K27ac and H3K9me3 in SEM (KMT2A::AFF1) cells under DOT1L inhibition, and the two marks answer this graph's standing question in opposite directions:

mark	direction under DOT1Li	scope	authors' own conclusion
H3K27ac	down	KEEs only; no global change	mediates the loss of accessibility and TF binding at KEEs
H3K9me3	up (modest trend)	general - KEEs, non-KEEs and a non-enhancer control	"do not explain the specific changes in TF binding at KEEs"

This is worth stating plainly because the graph has repeatedly found claims that blur fusion-target and genome-wide effects. Here one experiment contains both shapes, and the authors say which is which. It also constitutes a published, in-house counter-argument to the model that DOT1L inhibition works by permitting targeted heterochromatinisation of fusion targets [E4 against E5].

Why this mark is a brake on the fusion, not a consequence of it

The PAF1c route. SETDB1 was found as a novel PAF1-complex interactor by proteomics; stabilising that interaction with a CDC73 3YF mutant that cannot support AML growth, or over-expressing SETDB1, increases promoter H3K9me3 at Meis1 and Hoxa9 and reduces their transcription in AML cells 1. The follow-up shows genes directly bound by MLL-AF9 are significantly down-regulated on SETDB1 over-expression, that 193 of those genes have reduced promoter H3K9 methylation in AML patient samples relative to normal CD34+ cells, and that SETDB1 knockout in human THP-1 cells up-regulates an overlapping set 2. This graph already holds gene-paf1, gene-cdc73, gene-ctr9 and gene-leo1 as the machinery that puts the fusion on chromatin; the same complex carries the enzyme that shuts the fusion's targets down.

The SUV39H1 route. SUV39H1, the dominant H3K9 methyltransferase in haematopoiesis, is down-regulated in several leukaemias including MLL-r AML, and both its expression and genomic H3K9me3 occupancy are reduced in MLL-r leukaemia stem cells compared with their normal counterparts 3. The same work notes that SUV39H1 has been reported to interact with menin, which makes it the one H3K9 writer with a stated physical connection to this project's central druggable interface - a connection nobody has followed up under a menin inhibitor.

The direction matters therapeutically. If H3K9me3 restrains the fusion programme, then agents that lower it - and G9a/EHMT2 inhibitors such as UNC0638 lower H3K9me2 and H3K9me3 together 2 - are pointed the wrong way in this disease, whatever their effect on normal progenitors.

The eraser and reader arms, and what the graph already has

Erasers. The KDM4/JMJD2 family demethylates H3K9me2/3; gene-kdm4c is in this graph and KDM4 inhibition has been reported to attenuate leukaemia stem cells. No KDM4 experiment in a KMT2A-rearranged cell has reported H3K9me3 at fusion-bound loci.

Readers. HP1 proteins (CBX1/CBX3/CBX5) read H3K9me3. This graph has no entry for any of them, which is a real gap now visible from the mark side: the H3K9me3 story here runs writer-to-phenotype with the reader step entirely unwritten.

The H3.3 connection. ATRX and DAXX deposit histone variant H3.3 and maintain H3K9me3 at heterochromatin (gene-atrx, gene-daxx), and gene-hira records a 2026 CML result in which HIRA knockdown raises H3K9me3 through SETDB1. So the chaperone layer this graph already carries touches this mark in two directions, in two diseases, and in neither case in a KMT2A-rearranged cell.

A crosstalk route worth naming. KDM2B has been proposed to act as an H3K79me2/3 demethylase causing SIRT1 recruitment and gain of H3K9me3 [E4, citing prior work]; gene-kdm2b is in this graph as a PRC1.1 subunit. That places one protein at the junction of the H3K79, H3K9 and H2AK119ub arms, and it has never been tested in a KMT2A-rearranged cell.

The bounded absences

(KMT2A term set)[tiab] AND (H3K9me3 OR "H3K9 trimethylation")[tiab] returns 10 records on 2026-09-20 against 2,793 for H3K9me3[tiab] alone and 3,209 for the KMT2A set alone. PMID 31243293 is not among the ten 4, which is the second time in this beat that the strongest KMT2A::AFF1 measurement of a mark sat outside its own bounded query.

No H3K9me3 measurement exists under a menin inhibitor: the name-list-bounded drug query returns one irrelevant record, and three menin-inhibitor chromatin full texts contain the string zero times (counts and name list in mark-h3k27ac E6). Given that SUV39H1 is reported to interact with menin 3, that absence is more surprising than most.

No H3K9me3 measurement exists in infant material, in a B-lineage primary sample, or at fusion-bound loci in KMT2A::AFF1 - the SEM data 4 are enhancer-and-control regions, not a fusion-occupancy-anchored map.

Facts and figures

mark	H3K9me3
histone	H3
residue	K9, N-terminal tail
chemistry	trimethylation; mutually exclusive with H3K9ac on the same residue
variant link	ATRX-DAXX deposit H3.3 and maintain H3K9me3 at heterochromatin (gene-atrx, gene-daxx)
measured in kmt2a r	true
measured in kmt2a aff1	true
measured in infant material	false
measurement scope	GENERAL in the index fusion - increases at KEEs, non-KEEs and a non-enhancer control alike under DOT1L inhibition (PMID 31243293, SEM); LOCUS-RESOLVED in myeloid models at Meis1 and Hoxa9 promoters (PMIDs 29774127, 33054052)
direction in disease	tumour-suppressive at fusion targets: raising it lowers Hoxa9/Meis1; LSCs from MLL-r models carry less of it than normal counterparts
dot1l inhibitor effect	modest general increase in SEM (H3K9me3, PMID 31243293); targeted increase in murine MLL-AF9 at fusion-bound TSSs but measured as H3K9me2 (PMID 25822366)
menin inhibitor effect	never measured, despite a reported SUV39H1-menin interaction
spike in normalised	false
named in entries when written	19
mentions when written	61
count method	regex /\bH3K9me3/i over all 1,701 node JSON files, run 2026-09-20
abstract query count 2026 09 20	10
rule 80 changed the answer	true

writers named in sources

[
  "SETDB1 (Q15047, 1,291 aa; no gene entry in this graph as of 2026-09-20)",
  "SUV39H1 (O43463, 412 aa; no gene entry in this graph as of 2026-09-20)",
  "EHMT2/G9a (no gene entry; UNC0638 is the tool used)"
]

erasers

[
  "gene-kdm4c"
]

readers unwritten in this graph

[
  "CBX5/HP1alpha",
  "CBX1/HP1beta",
  "CBX3/HP1gamma"
]

abstract query misses

[
  "31243293"
]

How this could bite us back

H3K9 methyltransferase inhibitors are in clinical development, and in this disease the published direction is that H3K9 methylation restrains the fusion's targets - so a G9a or SETDB1 inhibitor given to a KMT2A-rearranged patient is a candidate for making the leukaemia worse, not better.
Conversely, an agent raising H3K9me3 globally would silence indiscriminately; the SEM experiment shows the mark rises at enhancers, non-enhancers and controls alike under a DOT1L inhibitor, so 'raise H3K9me3' is not an addressable intervention at fusion loci.
SUV39H1 declines with normal ageing in HSCs, so any therapeutic manipulation of this axis in an infant is acting on a system whose baseline is the opposite of the one most of the published data were collected in.
If DOT1L inhibition works partly by allowing heterochromatinisation, then combining it with an H3K9 methyltransferase inhibitor - a combination that looks attractive because both are 'epigenetic drugs' - is antagonistic by construction.

Still open

Is the H3K9me3 increase under DOT1L inhibition genuinely global? The SEM experiment tests selected loci plus controls without spike-in normalisation, which is precisely the design that cannot distinguish a global rise from no rise at all.
Does a menin inhibitor change H3K9me3 at fusion targets? SUV39H1 is reported to interact with menin, the reagents are standard, and no published study has looked in any system.
Which H3K9 methylation state actually matters at fusion targets - me2 or me3? The targeted result in murine MLL-AF9 is me2 and the untargeted result in human KMT2A::AFF1 is me3, and the two literatures do not address each other.
Does an HP1 protein read this mark at fusion-bound loci? This graph has no entry for CBX1, CBX3 or CBX5, and the whole H3K9me3 story in this disease is currently writer-to-phenotype with the reader missing.

Every source behind this entry (6)

E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In MLL-AF9-transformed AML cells, the PAF1 complex physically interacts with the H3K9 methyltransferase SETDB1 - an interaction stabilised by a CDC73_3YF mutant that cannot support AML cell growth - and over-expression of SETDB1 or stabilisation of the PAF1c-SETDB1 interaction increases promoter H3K9 trimethylation at Meis1 and Hoxa9 by ChIP while reducing their transcription; in human AML patients higher SETDB1 expression is associated with reduced HOXA9 and MEIS1.
PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression of Hoxa9 and Meis1 in acute myeloid leukemia. · Ropa J; Saha N; Chen Z; Serio J; Chen W; Mellacheruvu D; et al. · Oncotarget 2018
PMID 29774127 DOI
What this evidence cannot show
Read in full text (PMC5955148). Murine MLL-AF9-transformed myeloid cells; the human component is an expression correlation across patient cohorts, not a chromatin measurement in patients. The causal arm runs through over-expression and a gain-of-interaction mutant rather than through loss of SETDB1, so the physiological contribution of endogenous SETDB1 at these promoters is inferred. Published in Oncotarget, a journal whose editorial standards over this period have been questioned - the finding is reproduced by the same group in Haematologica [E2], which is why the pair is cited together.
Evidence that argues against this (1)
- SETDB1 is also reported to have oncogenic roles in other tumour types and the H3K9 methyltransferases display both tumour-suppressive and tumour-promoting behaviour in the same tissue, so a repressive effect at two loci does not establish a net direction for the enzyme in this disease. The companion paper makes this point about its own result. Ropa J; Saha N; Hu H; Peterson LF; Talpaz M; Muntean AG 2020
E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
SETDB1-mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukaemic transformation: genes directly bound by MLL-AF9 are significantly down-regulated on SETDB1 over-expression in mouse MLL-AF9 cells, 193 of those genes have reduced promoter H3K9 methylation in AML patient samples relative to normal human CD34+ cells, an overlapping set is up-regulated by CRISPR-Cas9 SETDB1 knockdown in human THP-1 cells, and the G9a inhibitor UNC0638 reduces both H3K9me2 and H3K9me3 in mouse lineage-negative bone marrow.
SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation. · Ropa J; Saha N; Hu H; Peterson LF; Talpaz M; Muntean AG · Haematologica 2020
PMID 33054052 DOI
What this evidence cannot show
Read in full text (PMC7556517). Mouse MLL-AF9 plus human THP-1 (KMT2A::MLLT3, myeloid) - no B-lineage and no KMT2A::AFF1. The patient-sample H3K9 methylation comparison is taken from a prior dataset rather than generated here, and it is H3K9 methylation broadly rather than H3K9me3 specifically. **UNC0638 is a G9a/EHMT2 inhibitor used as a proxy because no selective SETDB1 inhibitor exists**, so the pharmacological arm addresses H3K9 methyltransferases as a class and not SETDB1.
Evidence that argues against this (1)
- If H3K9 methylation were broadly repressive to the MLL-AF9 programme, DOT1L inhibition - which raises H3K9me3 - should be more effective than it is, and the SEM experiment shows the increase is general rather than targeted, so a global rise in the mark does not by itself silence fusion targets. Godfrey L; Crump NT; Thorne R; Lau IJ; Repapi E; Dimou D; et al. 2019
E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
SUV39H1, the dominant H3K9 methyltransferase in the haematopoietic system, is down-regulated in a variety of leukaemias including MLL-rearranged AML, and both decreased Suv39h1 expression and decreased genomic H3K9me3 occupancy are observed in leukaemia stem cells from MLL-rearranged models compared with their normal counterparts; SUV39H1 has also been reported to interact with menin.
SUV39H1 regulates the progression of MLL-AF9-induced acute myeloid leukemia. · Chu Y; Chen Y; Guo H; Li M; Wang B; Shi D; et al. · Oncogene 2020
PMID 33037410 DOI
What this evidence cannot show
Read in full text (PMC7728597). Mouse MLL-AF9 LSC and L-GMP populations plus in-house patient bone marrow CD34+ comparisons; myeloid throughout. The menin interaction is cited by these authors to prior work rather than demonstrated here, so it is recorded in this entry as a lead and not as a measurement. 'Genomic H3K9me3 occupancy' is a distributional statement across the stem-cell compartment, not a fusion-target-anchored map.
Evidence that argues against this (1)
- SUV39H1 expression declines with normal ageing in human and mouse HSCs, producing global H3K9me3 reduction independently of any leukaemia, so lower SUV39H1 and lower H3K9me3 in a leukaemia stem cell may reflect the proliferative or stem state rather than the fusion. Chu Y; Chen Y; Guo H; Li M; Wang B; Shi D; et al. 2020
E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In human SEM cells (KMT2A::AFF1 / MLL-AF4 B-ALL), DOT1L inhibition produces only a modest trend towards increased H3K9me3, and that increase is general - occurring at H3K79me2/3-marked enhancers (KEEs), at non-KEE enhancers and at a non-enhancer control region alike - so the authors conclude it does not explain the KEE-specific losses of H3K27ac, chromatin accessibility and transcription-factor binding seen in the same experiment.
DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation. · Godfrey L; Crump NT; Thorne R; Lau IJ; Repapi E; Dimou D; et al. · Nat Commun 2019
PMID 31243293 DOI
What this evidence cannot show
Read in full text (PMC6594956); the data are **Supplementary Fig. 4b-e** and the abstract names neither H3K9me3 nor the cell line, so this paper is absent from the bounded H3K9me3 x KMT2A abstract query. The measurement is ChIP at selected example loci plus control regions rather than a genome-wide H3K9me3 map, so 'general' is supported across the regions tested and is not a whole-genome statement. One cell line, one inhibitor, no spike-in normalisation - and for a mark expected to move globally, the absence of spike-in normalisation is a sharper limitation here than for H3K27ac.
Evidence that argues against this (1)
- The targeted model is on record from an independent group: in murine MLL-AF9 cells DOT1L inhibition recruits SIRT1 and SUV39H1 to MLL-AF9-bound TSSs and increases H3K9me2 there specifically. The two studies differ in methylation state (me2 versus me3), in lineage, in species and in whether the effect is targeted, and nobody has reconciled them. Chen CW; Koche RP; Sinha AU; Deshpande AJ; Zhu N; Eng R; et al. 2015
E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In mouse MLL-AF9 leukaemia cells, DOT1L inhibition increases H3K9 dimethylation and H3K27 trimethylation around the transcription start sites of MLL-AF9-bound genes, and Suv39h1 is required for the Sirt1-dependent H3K9 methylation and silencing of the MLL-AF9 leukaemic programme.
DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. · Chen CW; Koche RP; Sinha AU; Deshpande AJ; Zhu N; Eng R; et al. · Nat Med 2015
PMID 25822366 DOI
What this evidence cannot show
Read in full text (PMC4390532). The mark measured is H3K9me2 (antibody Abcam ab1220), **not H3K9me3**, so this evidence item is adjacent to rather than about the subject of this entry; it is included because it is the only targeted H3K9-methylation result in this disease and because it is the direct counterpart to [E4]. Murine myeloid; the human lines in that study were assayed for H3K9ac, not for H3K9 methylation.
Evidence that argues against this (1)
- The SEM experiment finds the H3K9me3 increase under DOT1L inhibition to be untargeted and explicitly insufficient to explain the locus-specific effects, and the two results are in different methylation states, different lineages and different species. Whether SIRT1-SUV39H1 silencing is a general consequence of DOT1L inhibition or a feature of the murine myeloid system is open. Godfrey L; Crump NT; Thorne R; Lau IJ; Repapi E; Dimou D; et al. 2019
E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
As of 2026-09-20 PubMed returns 10 records for the KMT2A term set intersected with (H3K9me3 OR 'H3K9 trimethylation')[tiab], against 2,793 for H3K9me3[tiab] alone and 3,209 for the KMT2A term set alone; PMID 31243293, which contains the only KMT2A::AFF1 H3K9me3 measurement found in this beat, is not among the ten.
NCBI E-utilities esearch over PubMed, run 2026-09-20 by the Q59 marks2 beat, with every querytranslation read back and recorded · US National Library of Medicine 2026
What this evidence cannot show
**Ten in titles and abstracts; supporting figures not searched by the query.** The bound was extended by reading fourteen core KMT2A-r chromatin full texts, which is how PMID 31243293's supplementary H3K9me3 panel was recovered. Fourteen full texts is not the whole literature. The name list was H3K9me3 and 'H3K9 trimethylation'; 'H3K9 methylation' bare was not run against the KMT2A set and would widen the count, and would also pull in me1 and me2. Querytranslations were read back and none contained a [UID] term.
Evidence that argues against this (1)
- Several of the ten records are on-topic and were rejected for this entry rather than being absent: a TWIST1 leukaemia-stem-cell paper, a KDM4 inhibitor study, a PBX3 stem-cell paper and a CXXC-domain study each mention the mark incidentally without measuring it at fusion-bound loci. A count of ten is not ten measurements. Ropa J; Saha N; Hu H; Peterson LF; Talpaz M; Muntean AG 2020

Connected to

← regulatesASB7 (Q9H672) - the brake on H3K9me3's own positive feedback loop, released by CDK1 in mitosis, and it reached this graph as the flattest dependency in the read queue
NEGATIVE regulator, acting on the writer rather than the mark: CUL5-ASB7 ubiquitinates SUV39H1 for degradation, and ASB7 is recruited to heterochromatin by HP1
← related toThe six open read-queue members split three rejected and three earning entries - and the flattest dependency in the set, ASB7, turns out to be a negative regulator of H3K9me3 via SUV39H1 degradation
ASB7 is a negative regulator of this mark, degrading the writer SUV39H1 - a control layer by writer DEGRADATION that neither side of this graph's H3K9 conflict models
← related toH3K9ac - the mark KMT2A fusions pile up on their own targets, the one the AF9 reader actually binds, and the one a DOT1L inhibitor strips off first
same residue, mutually exclusive; the DOT1L-inhibitor switch runs acetyl-to-methyl at fusion targets
← causesPAF1 — pan-essential subunit of a complex the fusion needs, where the window is in the interface and not in the protein
the PAF1c-SETDB1 interaction deposits promoter H3K9me3 at Meis1 and Hoxa9
← regulatesCDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion
the CDC73_3YF mutant stabilises the PAF1c-SETDB1 interaction and raises the mark
inhibits →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it
promoter H3K9me3 represses Hoxa9 in MLL-AF9 cells
inhibits →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed
promoter H3K9me3 represses Meis1 in MLL-AF9 cells
← causesPinometostat (EPZ-5676) — the DOT1L inhibitor, and the most instructive failure in this field
modest GENERAL increase in SEM (KMT2A::AFF1) - at KEEs, non-KEEs and controls alike
related to →H3K27ac - named in 40 entries with no entry of its own, and the strongest KMT2A::AFF1 measurement of it is invisible to every abstract search
same experiment, same cells: H3K9me3 up generally where H3K27ac falls at KEEs only
related to →KDM4C (JMJD2C/GASC1) — recruited by the retained KMT2A N-terminus, drugged in a KMT2A::AFF1 line, and invisible to CRISPR
KDM4-family demethylases erase H3K9me2/3; none assayed at fusion-bound loci
related to →ATRX - DAXX's partner and the other arm of H3.3 deposition; in this disease its only signal is in the four lymphoid cell lines
ATRX-DAXX maintain H3K9me3 at heterochromatin alongside H3.3 deposition
related to →KDM2B — 513 potent ChEMBL rows that are mostly patent bins, and no structure of the domain they claim to inhibit
proposed H3K79me2/3 demethylase whose action recruits SIRT1 and gains H3K9me3 - untested in KMT2A-r
expressed in →KMT2A-rearranged acute myeloid leukaemia in children and infants
reduced H3K9me3 occupancy in leukaemia stem cells from MLL-r models
part of →Plain-English: chromatin and epigenetics — the sticky notes on the DNA, and which ones matter here
layman explainer for the mark layer
related to →The stem-like self-renewal state — a limited stem-cell module grafted onto a committed cell
the LSC compartment in MLL-r models carries less H3K9me3 than its normal counterpart
← supportsRule 80 measured: the abstract index missed the best KMT2A measurement for three marks out of seven, and confirmed the absence for the other four
supplies the counted bound and the rule-80 rescue for this mark
← related toEHMT2 / G9a - the H3K9me1/2 writer that sets whether the KMT2A LOCUS ITSELF rearranges, and whose loss delays MLL-AF9 AML in a supplementary figure nobody can find
G9a writes H3K9me1/me2 and NOT me3; the two marks point opposite ways in MLL-fusion AML
← regulatesDEK - a chromatin architectural protein that gatekeeps H3.3 and boosts HP1alpha, is a fusion partner in its own right, and is the substrate behind this graph's third CK2 route
DEK binds HP1alpha directly and MARKEDLY ENHANCES its binding to H3K9me3
← related toREST / NRSF - the transcription factor that delivers G9a to chromatin through MED19 and MED26, is a paediatric cancer gene, and is the worst search token in this corpus
the mark family REST delivers is H3K9me1/me2 via EHMT1/EHMT2, not me3
← related toH3K9me1 - the only H3K9 state whose level at the KMT2A breakpoint cluster region has ever been measured, and it is LOW there until KDM3B is removed
me1 is the substrate pool SUV39H uses for me3; the two marks' disease directions are opposite and the opposition resolves on locus and stage, not on error
← related toH3K9me2 - named sixty times in this graph with no entry of its own, the mark that defines the lamina-associated domains the fusion's targets sit beside, and the only H3K9 methylation state ever measured at a KMT2A fusion's own binding sites
answers mark-h3k9me3's open question in part: the TARGETED H3K9-methylation result at fusion-bound TSSs is me2, not me3
← related toThe H3K9me1/2-CTCF brake: a KDM3B-G9a balance keeps the KMT2A breakpoint cluster region methyl-poor and CTCF-bound, and losing either end makes the locus amplify and rearrange - in epithelium, in primary cord-blood progenitors and in mice
the unresolved tension: that entry argues H3K9 methylation restrains the fusion programme at its TARGET genes, this one that H3K9me1/2 promotes rearrangement of the KMT2A GENE. Mark, locus and disease stage all differ
← related toUNC0642 - the G9a/GLP chemical probe that abolished doxorubicin-induced Kmt2a copy gain in mice, and the one intervention in this beat that has been given to an animal
the collision point: that entry argues lowering H3K9 methylation is the wrong direction in KMT2A-r disease, and this compound's predecessor lowered me3 as well as me2
← related toThe one experiment that would separate the H3K9me1/2 rearrangement brake from H3K9me3 was run, deposited as eight public samples, and reported nowhere in the paper
the deposited-but-unreported H3K9me3 arm is the measurement that tests whether mark identity resolves this entry's conflict with the me1/me2 mechanism
← supportsRUN: the eight unreported H3K9me3 samples of GSE210480, read at the KMT2A CTCF element - H3K9me3 does not move where H3K9me1 moves 3.9-fold, and the me1/me2 positive controls passed
H3K9me3 does not follow the KDM3B-G9a balance at this element, so mark identity can reconcile the two directions
← related toThe resolution floor: every deposited H3K9 track in GSE210480 is 1,000 bp binned, so the 147 bp exon-11 question cannot be answered from the processed files - and the planned analysis that asked for 500 bp windows was asking for something that is not there
H3K9me3 is a broad-domain mark, so a 1 kb bin is close to its natural feature size
← testsThe experiment the public data cannot supply: H3K9me1/2/3 and CTCF at the KMT2A exon-11 anchor in a cord-blood CD34+ progenitor, with and without KDM3B depletion
whether the H3K9me3 null at this anchor holds in a haematopoietic cell, which is where mark-h3k9me3's argument lives
← supportsThe H3K9me3 null that appears to exonerate prophylactic G9a inhibition was measured in retinal pigment epithelium, at 1 kb resolution, with n = 2 - and the warning it appears to lift lives in a leukaemic blast
its warning is at fusion-target promoters in leukaemic cells and is untouched by an epithelial CTCF-anchor null
← regulatesSUV39H1 (O43463, KMT1A) - the H3K9me3 writer: a menin effector whose binding region OVERLAPS the drug pocket at its N-terminus, a tumour suppressor in MLL-AF9 AML, recruited to double-strand breaks by CTCF, and never localised at the KMT2A locus in any cell type
writes H3K9me3 - the canonical constitutive-heterochromatin H3K9 trimethyltransferase
← regulatesSETDB1 (Q15047, KMT1E/ESET) - the second H3K9me3 writer: it represses the fusion's own targets via the PAF1 complex, it is required in fetal liver HSPCs and in leukaemic stem cells, and it is a broad dependency in half the CRISPR panel - three published directions that do not agree
writes H3K9me3; the H3K9me3-specific methyltransferase of the pair, non-pericentromeric and nucleolus-excluded
← bindsCBX5 / HP1-alpha (P45973, 191 aa) - the H3K9me3 reader that recruits the writer, the writer's destroyer and the second writer; and the one member of that circuit with a published pro-leukaemic role, as part of an MLL leukaemia stem-cell programme that immortalises myeloid progenitors WITHOUT Hoxa or Meis
chromodomain reader of H3K9me2/me3 (aa 20-78); the reader whose occupancy, not just writer activity, sets the mark's level at a locus
← related toNo H3K9me3 writer and no H3K9me3 reader has ever been localised at the KMT2A locus IN THE PUBLISHED LITERATURE, in any cell type: 20 queries, 5 alias spellings, 0 on-topic records - and CORRECTED 2026-09-22: the SUV39H1 half is no longer unanswerable from archives. ENCODE still holds zero SUV39H1 experiments (verified by three routes with controls), but GEO holds two deposits, and Q114 read both at this locus and found the writer ABSENT
the mark has been measured at this locus; its writers and its reader have not, in any cell type
← testsThe deposit this graph filed as 'four SUV39H1 ChIP-seqs' is actually 77 samples in MCF-7 carrying the ENTIRE H3K9 axis in one cell type and one pipeline - writer SUV39H1, writer G9a/EHMT2, reader HP1-alpha/CBX5 (wild-type AND two phospho-mutants), co-repressor KAP1/TRIM28, erasers KDM4B and KDM4C, the mark H3K9me3, and an shKDM4B+shKDM4C eraser-knockdown arm
8 H3K9me3 samples incl. an shKDM4B+shKDM4C eraser-knockdown arm, same cells as the writer
← related toThe rarest thing in the deposit, measured: across 59,821 CTCF anchors in the SAME nuclei, SUV39H1 occupancy and H3K9me3 correlate at Spearman 0.148 and 0.078 - and a quarter to two-fifths of the enzyme's own strongest sites carry no more of its mark than the median anchor
first direct writer-versus-mark measurement in a human cell in this corpus, and it is weak
← testsIn patient-derived H3K27M glioma, baseline H3K9me3 over the 7,466 bp KMT2A breakpoint cluster core sits at the 7.8th and 28.5th percentile of 59,821 width-matched CTCF-anchor windows (0.56x and 0.90x the random-tile median) - the methyl-poor-BCR pattern this graph found in epithelium and in a blood line, now in a third lineage and for the trimethyl state
baseline H3K9me3 over the 7,466 bp BCR core, 7.78th and 28.52nd percentile of class-matched anchors
← related toBounded with every archive and every route named: after both public SUV39H1 deposits were read this cycle, there is still NO SUV39H1 occupancy measurement in any haematopoietic cell, any KMT2A-rearranged cell, or any damage state - in ENCODE (three routes, zero), ChIP-Atlas (one deposit, MCF-7 only) or GEO (two deposits, glioma and breast)
the writer in this mark's dispute has never been placed in a cell of the right lineage
← related toThe H3K9me3 this graph argues about at the KMT2A exon-11 anchor is not deposited by SUV39H1: in SU-DIPG13 the mark sits at the 57.8th percentile of class-matched CTCF anchors while the writer reads an EXPLICIT ZERO in the same nuclei, and genome-wide the two barely track each other (Spearman 0.148, 0.078)
if true, the mark at this element is not the SUV39H1 product this graph's dispute assumes
← testsIn MCF-7 the two signals point in opposite directions over the same 90 kb: H3K9me3 sits at the 15.8th and 10.3rd percentile of 56,171 same-cell CTCF anchors across the KMT2A gene body (0.82x and 0.65x the random-tile mean) while SUV39H1 sits at the 81.7th-86.8th in all four of its tracks - and the 147 bp anchor carries ZERO H3K9me3 in the minus-estradiol track
H3K9me3 at the 15.8th and 10.3rd percentile of same-cell CTCF anchors over the 90 kb KMT2A gene body
← regulatesKDM4B (JMJD2B) - the weakest of the four H3K9me3 demethylases, one of the two erasers knocked down in the only KDM4-perturbation arm in any archive that touches this mark
JmjC demethylase of H3K9me3; UniProt records it as the weakest of KDM4A-D at that substrate
← related toTHE DEFLATING NULL, RUN: matching on gene length AND MCF-7 expression roughly HALVES the H3K9me3 depletion over the KMT2A gene body - from the 7.6th-15.0th percentile of class-matched CTCF anchors to the 18.2nd-23.4th of 385 matched transcribed gene bodies - so the methyl-poor breakpoint domain is partly a fact about transcription and does not dissolve into one
first transcription-matched null for this mark at the KMT2A locus in any cell type
← related toRUN, with its positive control: knocking down KDM4B and KDM4C together raises H3K9me3 at the +1 nucleosome of 2,000 active promoters by 35.7 percentile points, moves the KMT2A promoter's +1 nucleosome by the same 35.3, and moves the 90 kb KMT2A gene body 5.05 points the WRONG way - so the methyl-poor domain is not an erasure product
the only eraser perturbation in any public archive with an H3K9me3 occupancy readout, read at the KMT2A locus for the first time
← related toTHE POSITIVE RESULT: the writer G9a, the reader HP1a and the scaffold KAP1 all sit on the KMT2A PROMOTER in MCF-7 at the 87.6th-98.9th percentile of 2,000 ACTIVE promoters - surviving the control that says an active promoter is ChIP-hot for everything - while none of the three is above the 75th percentile at the exon-11 anchor 52 kb away
the reader and the scaffold for this mark are at the KMT2A promoter while the mark itself reads an explicit 0.0000 at the exon-11 anchor in five of six MCF-7 tracks
← related toRUN: endogenous HP1a/CBX5 is DEPLETED at the exon-11 anchor (median 23.94th percentile) and has the lowest KMT2A gene-body reading of any protein in the panel (30.16) - while the phosphomimetic Bio-ChIP mutant 4E reads higher than the phospho-compromised 4A at all seven intervals AND that difference falls inside the genome-wide interquartile range of the same comparison, so it carries no information
reader and mark agree in direction over the KMT2A gene body - CBX5 at 30.16 and H3K9me3 at 2.56-15.00 across eight tracks - and they are the only two antigens in the panel that read the locus down
← depends onBARD1 (Q99728, 777 aa) - BRCA1's obligate partner, and the member of the cascade that actually touches the chromatin: its PxVxL motif at 569-573 binds HP1, and CTCF binds BARD1 rather than BRCA1 in an undamaged cell
reaches break chromatin via the PLVLI 569-573 contact with the HP1 chromoshadow domain
← bindsCBX3 / HP1-gamma (Q13185, 183 aa) - the EUCHROMATIC HP1 paralogue, and the one CTCF actually prefers: the reader that carries BRCA1/BARD1 onto H3K9-methylated break chromatin, flat in DepMap, and a fusion partner in one KMT2A::AFDN AML patient
chromo domain 30-88 reads H3K9me2/me3 at the break
← depends onThe CTCF licensing cascade: CTCF recruits HP1-gamma, KAP1, SUV39H1, SETDB1 and KDM5A to a break, that repressive chromatin licenses EARLY BRCA1/BARD1, and early BRCA1/BARD1 licenses EXO1/DNA2 long-range resection - measured entirely in U2OS and HEK-293T, with engineered breaks and one etoposide arm
the licence is H3K9me GAINED and H3K4me LOST as a pair, not a single mark level