SETDB1 (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

This is real experimental data — atoms placed by crystallography or cryo-EM, deposited by the people who did the experiment.

• THE DEPENDENCY FIGURE IS NOT A TARGET NOMINATION AND THIS ENTRY SAYS SO IN ITS OWN DATA BLOCK. SETDB1 is below -0.5 in 50.4% of 1,258 CRISPR screens and in 63.3% of the 147 blood screens - deeper in blood than MEN1 in the same call. A gene needed by half of all screened cancer lines is a broad dependency, and floor compression at that depth also means a fusion-selectivity contrast on it would be close to uninterpretable.
• Essential-function toxicity is documented in exactly the wrong compartment. Setdb1 deletion rapidly depletes adult murine HSPCs (PMID 27301860) and compromises murine FETAL LIVER HSPCs with impaired lymphoid development (PMID 39689172). The patient is an infant whose lymphoid system is being built from that compartment, so a SETDB1 inhibitor is a marrow-and-lymphoid-toxicity proposal before it is anything else.
• The sign of a SETDB1 intervention in this disease is unknown and this graph previously held only the limb that supports one answer. Raising SETDB1 suppresses MLL-fusion targets (PMID 33054052); deleting it kills leukaemic stem cells (PMID 27301860). Either direction has a published rationale and neither has been tested against the other's endpoint in one system.
• There is no selective chemical matter, and that is not the obstacle. SETDB1[tiab] AND degrader[tiab] returns 2 records and both fail a title check (a Smurf1 paper and a KDM5B PROTAC); SETDB1[tiab] AND "chemical probe"[tiab] returns 0. Building a probe would not resolve any of the three contradictory directions above, because the contradiction is in the biology and not in the pharmacology.
• Perturbing the mark is not perturbing one element. SETDB1 loss in fetal HSPCs opens cryptic enhancers genome-wide that PU.1 already occupies (PMID 39689172), and SETDB1's own occupancy sits on transcribed, H3K36me3-high ZNF 3' exons whose H3K9me3 loss causes DNA damage (PMID 27029610). A strategy aimed at H3K9me3 at one CTCF anchor has two documented routes to genome-wide consequences.

1. Which leukaemia model supplied the leukaemic stem cells that Setdb1 deletion depleted in PMID 27301860? The abstract does not say, and the answer decides whether directions 1 and 2 of this entry are a contradiction within KMT2A-fusion biology or two facts about different diseases. It is one paper read.
2. Does SETDB1 occupy the KMT2A locus in a blood cell? ANSWERED for K562 this cycle - no called peak in the gene or within 50 kb, in three peak sets from two labs. What remains open is whether that is a resting-state property or an absence full stop, because both writers are recruited to breaks transiently and no archive holds a damage arm at this locus; and whether a KMT2A-rearranged line would read the same, which needs wet work.
3. Is the lymphoid defect in Setdb1-deficient fetal liver HSPCs a B-lineage defect specifically, and at which stage? The compartment is this disease's putative origin and the abstract says only 'impaired lymphoid development'.
4. Does SETDB1 sit on cryptic enhancers in a KMT2A::AFF1 B-lymphoblast as it does in murine fetal HSPCs? The finding that PU.1 binds H3K9me3-marked cryptic enhancers in wild-type fetal HSPCs (PMID 39689172) is a mechanism by which a mark change at any element could change transcription-factor access without changing transcription, and this graph has no such measurement.
5. Is the PAF1c-SETDB1 interaction independently replicated? Both papers establishing it come from one group, and it is the hinge of mark-h3k9me3's argument that H3K9 methylation restrains the fusion programme.

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   SETDB1 is UniProt Q15047, entry name SETB1_HUMAN, 1,291 amino acids, primary gene name SETDB1 with synonyms ESET, KIAA0067 and KMT1E, HGNC:10761 at 1q21.3, Ensembl ENSG00000143379; its feature table annotates three Tudor domains at 201-251 (degenerate), 257-320 and 347-403, an MBD at 594-665, pre-SET at 727-800, a bifurcated SET at 803-1266 and post-SET at 1275-1291; its coded subcellular locations are Nucleus, Cytoplasm and Chromosome, with notes that it associates with non-pericentromeric chromatin, is recruited to H3K9me and H3K19ac marks, and is excluded from nucleoli and islands of condensed chromatin; and it cross-references 25 PDB entries.

   UniProtKB Q15047 (SETB1_HUMAN) - Histone-lysine N-methyltransferase SETDB1, Homo sapiens; with HGNC:10761 · UniProt Consortium; HUGO Gene Nomenclature Committee · UniProt Knowledgebase / HGNC 2026
   ▸What this evidence cannot show

   Exactly one reviewed human record was returned by gene_exact and its gene_primary was read back. The 1,291 aa length is a genuine discriminator against every other H3K9 methyltransferase in this graph (SUV39H1 412, SUV39H2 410, EHMT2 1,210), so unlike the SUV39H1/H2 pair the length assertion here does real work. The subnuclear notes are UniProt's summaries of individual papers and each rests on a single PMID; none was independently read for this entry except PubMed:27029610, which is [E10].

   ▸Evidence that argues against this (2)

   • Rule 91: the 'recruited to H3K9me and H3K19ac' note rests on one PMID and 'H3K19ac' is an unusual mark to see cited for a writer's recruitment - it is not a mark this graph holds an entry for and it was not verified here. Treat the recruitment half of the note as uncoded for present purposes.
   • A 25-entry PDB footprint says this protein crystallises well, not that it is druggable. No entity, construct, span or resolution was checked, and the Tudor-domain fragment screens in that list are structures of one small domain rather than of the catalytic machine.
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In MOUSE MLL-AF9 cells and human THP-1, SETDB1-mediated H3K9 methylation suppresses MLL-fusion target expression and leukaemic transformation: genes directly bound by MLL-AF9 are significantly down-regulated on SETDB1 over-expression; 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, et al. · Haematologica 2020
   PMID 33054052DOI
   ▸What this evidence cannot show

   Mouse MLL-AF9 and human THP-1 (KMT2A::MLLT3) - both MYELOID, neither the index fusion, no B-lineage and no infant material (rule 73). The gain-of-function arm is over-expression of a methyltransferase, which can act through non-histone substrates. Already cited four times in this graph (drug-unc0642, mark-h3k9me1, mark-h3k9me3, mechanism-h3k9me1-2-ctcf-balance-gates-kmt2a-rearrangement), so the conclusion is not new here - what is new is that it is now stated beside [E4] and [E6], which point the other way.

   ▸Evidence that argues against this (2)

   • [E4] is the direct opposition and it is in the same lineage: Setdb1 deletion caused rapid depletion of leukaemic stem cells as well as HSPCs (PMID 27301860, Blood). A gene whose over-expression suppresses transformation and whose deletion kills the leukaemic stem cell cannot be carrying a single therapeutic sign, and neither paper measures the other's endpoint.
   • The 193-gene patient comparison is AML samples against normal CD34+ cells, so it confounds fusion status with differentiation state - AML blasts and CD34+ progenitors differ in H3K9 methylation for many reasons, and the comparison does not isolate the fusion.
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The PAF1 complex recruits SETDB1 to fusion targets. In MLL-AF9-transformed AML cells the PAF1 complex physically interacts with 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, et al. · Oncotarget 2018
   PMID 29774127DOI
   ▸What this evidence cannot show

   Mouse MLL-AF9 myeloid cells. Already cited three times here (gene-cdc73, gene-paf1, mark-h3k9me3) and included in this entry because SETDB1 had no entry of its own to carry it. The CDC73_3YF mutant is a phospho-tyrosine mutant, so the recruitment is conditional on a signalling state, and Oncotarget is a journal whose editorial standing in this period is contested - the result's replication is [E2] from the same group, which is not independent.

   ▸Evidence that argues against this (2)

   • The same PAF1c subunit recruits the OTHER H3K9me3 writer in non-haematopoietic cells: parafibromin/CDC73 aa 128-227 recruits SUV39H1 to the cyclin D1 promoter (PMID 19906718), and SHP2 dephosphorylation of the same tyrosines flips parafibromin to beta-catenin-mediated activation (PMID 21726809). So CDC73's phospho-state selects between two writers and an activator, and which writer arrives in a KMT2A::AFF1 B-lymphoblast is not established by either literature.
   • Both papers on this axis come from one group, so the PAF1c-SETDB1 interaction has no independent replication known to this project, and it is the mechanistic hinge of mark-h3k9me3's whole restraining argument.
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   Setdb1 is essential for murine haematopoietic stem and progenitor cells AND for leukaemic stem cells. Setdb1 is the first H3K9 methyltransferase shown to be essential for the maintenance of HSPCs in mice; its deletion caused the rapid depletion of HSPCs as well as of LEUKAEMIC STEM CELLS; in contrast to embryonic stem cells, endogenous retroviral elements were largely repressed in Setdb1-deficient HSPCs, and instead a list of non-haematopoietic genes was ectopically activated after reductions in H3K9me3, including the key gluconeogenic enzyme genes Fbp1 and Fbp2; the ectopic gluconeogenic enzymes antagonised glycolysis and impaired ATP production, compromising the repopulating capacity of HSPCs.

   Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes. · Koide S, Oshima M, Takubo K, Yamazaki S, et al. · Blood 2016
   PMID 27301860DOI
   ▸What this evidence cannot show

   Abstract level; murine, adult haematopoiesis, and the abstract does not state which leukaemia model the depleted leukaemic stem cells came from - so 'leukaemic stem cells' here cannot be attributed to a KMT2A fusion without reading the paper. That single uncertainty is load-bearing for this entry's central tension and is the first thing a follow-up should close.

   ▸Evidence that argues against this (2)

   • Not knowing the leukaemia model is a real limit on how far this opposes [E2]. If the LSCs were from a non-KMT2A model, the contradiction is between 'SETDB1 restrains MLL-fusion targets' and 'SETDB1 is needed by some other leukaemia's stem cells', which is a weaker conflict. The entry states the tension at the strength the abstract supports and no further.
   • The mechanism found is metabolic - gluconeogenic enzymes antagonising glycolysis - not transcriptional de-repression of a fusion programme. A metabolic route means the HSPC phenotype could be unrelated to the H3K9me3 function this graph cares about, and the mark change is the upstream event rather than the measured cause.
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In MOUSE FETAL LIVER HSPCs - the compartment this graph holds as the index disease's origin - deletion of Setdb1 compromises stem-cell function, enhances myeloerythroid differentiation and IMPAIRS LYMPHOID DEVELOPMENT; Setdb1-deficient fetal HSPCs show reduced quiescence and increased proliferation with a lineage-biased transcriptional programme; and the mechanism is loss of H3K9me3 with increased chromatin accessibility at cryptic enhancers that haematopoietic transcription factors such as PU.1 already bind in wild-type HSPCs despite the H3K9me3 status, so SETDB1 restricts activation of non-physiological TF binding sites.

   Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers. · Kazerani M, Cernilogar F, Pasquarella A, Hinterberger M, et al. · Proceedings of the National Academy of Sciences 2024
   PMID 39689172DOI
   ▸What this evidence cannot show

   Abstract level; murine fetal liver, no human material, no fusion. 'Impaired lymphoid development' is the phenotype most relevant to this graph and it is one clause of an abstract - the magnitude, the stage at which lymphoid output fails, and whether B-lineage specifically is affected are not established here.

   ▸Evidence that argues against this (2)

   • It points the opposite way to any therapeutic use of a SETDB1 inhibitor in an infant. The compartment in which SETDB1 is required for lymphoid development is the compartment the index fusion is thought to arise in, and the patient is a child whose normal fetal-derived haematopoiesis is still being built.
   • It also complicates the mark's interpretation at any single locus. If H3K9me3 in fetal HSPCs sits over enhancers that PU.1 already occupies, then H3K9me3 there is not a simple off-switch, and a change in the mark at one element cannot be read as a change in that element's activity.
6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   SETDB1 is a broad dependency across the CRISPR panel, not a selective one. Flattening every tissue block of the DepMap essentiality payload gives 1,258 screens with a gene effect, mean -0.5288, median -0.5025, minimum -2.5919, with 50.4% of lines below -0.5 and 6.1% below -1.0; in the 147 screens from the hematopoietic and lymphoid blocks the mean is -0.6491 with 63.3% below -0.5. In the same call and the same data version, MEN1 gives mean -0.3616 with 28.9% below -0.5 and a blood mean of -0.5831, while SUV39H1 gives -0.0575 and CBX5 -0.083.

   Open Targets Platform GraphQL API, target.depMapEssentiality with all tissue blocks flattened, plus meta.dataVersion · Open Targets Platform; Broad Institute DepMap · Open Targets Platform 2026
   ▸What this evidence cannot show

   Rule 83: the payload carries no DepMap release identifier, only the Open Targets data version (year 26, month 06). Rule 84: no median-split proportion is reported and the fractions are against absolute thresholds. The side-by-side with MEN1 is NOT a selectivity comparison - a pan-panel mean is the wrong statistic for that, and this pair is exactly the broad-versus-selective case the rule warns about. The panel contains no infant KMT2A::AFF1 line. Panel-maximum guard cleared at 1,258 screens and a live POLR2A zero-screen control was run in the same call.

   ▸Evidence that argues against this (2)

   • A broad dependency is evidence against a therapeutic window and is NOT evidence about the fusion biology in either direction. It is compatible with SETDB1 restraining fusion targets (a transcriptional effect over days) and with SETDB1 being needed for proliferation (a viability effect over three weeks), and it cannot arbitrate between [E2] and [E4].
   • Floor compression: with half the panel below -0.5 and the blood arm deeper still, there is little dynamic range left in which fusion-selectivity could appear, so a KMT2A-rearranged-versus-comparator contrast on this gene would be close to uninterpretable - the same defect this graph records for HCFC1 and KAT8.
7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   SETDB1 abundance is degradation-controlled, and TRIM28/KAP1 is the protector. TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with the telomeric shelterin/telosome complex; knocking down TRIM28 in ALT cells delayed cell growth, decreased C-circle levels, increased the frequency of ALT-associated PML bodies, lengthened telomeres and increased telomere sister-chromatid exchange; and mechanistically TRIM28 protects SETDB1 from degradation, thereby maintaining the H3K9me3 heterochromatin state of telomeric DNA.

   TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. · Wang C, Songyang Z, Huang Y · Cell & Bioscience 2021
   PMID 34330324DOI
   ▸What this evidence cannot show

   Abstract level; ALT tumour cells, telomeres, not haematopoietic and not this locus. The abstract does not name the ligase that degrades SETDB1, so the parallel with CUL5-ASB7 on SUV39H1 is structural rather than mechanistic - and this entry does not claim ASB7 acts on SETDB1.

   ▸Evidence that argues against this (1)

   • The compartment is telomeric heterochromatin in ALT-positive cells, which is a specialised state, and the readouts are ALT phenotypes. Whether SETDB1 abundance is degradation-limited in a haematopoietic cell at a euchromatic locus is untested, so this supports only the general point that a mark level can move without an enzyme-activity change.
8. E8strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The reader recruits this writer, and the reader is HP1-alpha specifically. The CHAMP1 complex - CHAMP1, POGZ and HP1-alpha - is enriched in heterochromatin, promotes heterochromatin assembly at multiple chromosomal sites including centromeres and telomeres, and promotes homology-directed repair of double-strand breaks in those regions; the complex binds and recruits the writer methyltransferase SETDB1 to heterochromatin regions and is required for efficient DSB repair there; and peripheral blood lymphocytes from individuals with CHAMP1 syndrome, an inherited neurological disorder caused by heterozygous CHAMP1 mutations, exhibit defective heterochromatin clustering and defective DSB repair.

   CHAMP1 complex directs heterochromatin assembly and promotes homology-directed DNA repair. · Li F, Zhang T, Syed A, Elbakry A, et al. · Nature Communications 2025
   PMID 39962076DOI
   ▸What this evidence cannot show

   Abstract level; the cell lines used for the mechanism are not named in the abstract, and the only human primary material is peripheral blood lymphocytes from CHAMP1-syndrome individuals used as a repair-defect readout, not as a SETDB1-occupancy measurement. The recruitment is to heterochromatin, not to a euchromatic loop anchor. A 2025 paper with no replication known to this project.

   ▸Evidence that argues against this (2)

   • It places SETDB1 recruitment by HP1-alpha in HETEROCHROMATIN, which is close to the opposite of the KMT2A exon-11 element's chromatin state - an active, transcribed, CTCF/cohesin-bound anchor. A heterochromatin-assembly complex need not operate there at all.
   • A review of this literature notes that children with CHAMP1 syndrome have developed leukaemia, suggesting CHAMP1 mutations may be a cancer risk factor (PMID 42748571, DNA Repair 2026, a review and used only as a map). That is a reason to look, not evidence of a mechanism, and the leukaemias are not reported as KMT2A-rearranged.
9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   CTCF recruits SETDB1 to double-strand breaks alongside SUV39H1. In U2OS and HEK-293T cells, CTCF recruits the repressive chromatin proteins HP1-gamma, KAP1, SUV39H1, SETDB1 and KDM5A, enabling rapid accumulation of BRCA1/BARD1 at DSBs; CTCF depletion abrogates the enrichment of these proteins with loss of H3K9 methylation at DSBs, and depriving any one component compromises the accumulation of the others and of BRCA1/BARD1, abrogating EXO1/DNA2 recruitment and end resection.

   CTCF primes repressive chromatin for rapid BRCA1/BARD1 recruitment to drive homologous recombination repair of DNA double-strand breaks. · Hwang SY, Choi D, Choi MJ, Jo HR, et al. · Nucleic Acids Research 2026
   PMID 42475683DOI
   ▸What this evidence cannot show

   Abstract plus methods read from PMC13384258; systems are HEK-293T and U2OS DSB reporter lines with enzyme-induced breaks (AsiSI, FokI), so no endogenous locus and no blood cell. The HP1 paralogue named is HP1-gamma/CBX3 and is not transferred to CBX5 here. Reagents include etoposide and BIX-01294, a G9a/GLP inhibitor.

   ▸Evidence that argues against this (1)

   • It makes SETDB1 and SUV39H1 indistinguishable at a break - both are recruited by the same protein in the same cascade - so the DSB route cannot be used to argue which writer matters at the KMT2A anchor. Only the resting-state compartment difference separates them, and that is a prior, not a measurement.
10. E10strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    SETDB1's one uncontroversial genomic address is the 3' exons of zinc-finger genes, co-occupied with TRIM28, ZNF274 and ATRX. A comprehensive ChIP-sequencing study of ATRX in multiple human cell lines identified the 3' exons of ZNF genes as a class of ATRX targets; these regions carry an atypical signature - transcriptionally active, high H3K36me3 and paradoxically enriched in H3K9me3 - and are co-occupied by SETDB1, TRIM28 and ZNF274, which form a complex with ATRX; CRISPR loss of ATRX or ZNF274 reduces H3K9me3 at the ZNF 3' exons, and cells with reduced H3K9me3 there show increased DNA damage.

    ATRX binds to atypical chromatin domains at the 3' exons of zinc finger genes to preserve H3K9me3 enrichment. · Valle-Garcia D, Qadeer ZA, McHugh DS, Ghiraldini FG, et al. · Epigenetics 2016
    PMID 27029610DOI
    ▸What this evidence cannot show

    Abstract level. This is cited here for two reasons: it is UniProt's source for SETDB1's non-pericentromeric chromatin assignment, and it is the basis for the ZNF274 3'-exon positive control used in this beat's occupancy analysis. The co-occupancy claim is from ChIP-seq overlap plus complex formation, and the loss-of-function arms are ATRX and ZNF274 rather than SETDB1 itself.

    ▸Evidence that argues against this (1)

    • A transcribed region that is paradoxically H3K9me3-enriched is a warning about this whole beat's inference: H3K9me3 and active transcription coexist at ZNF 3' exons, so finding H3K9me3 at a transcribed element like the KMT2A gene body would not by itself mean the element is silenced, and finding none would not mean the writers are absent from the gene.

• ← co-occurs withBRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy

  SETDB1 is one of the repressive chromatin proteins in the same CTCF-primed DSB cascade

• ← related toSUV39H1 (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

  the two H3K9me3 writers, separable on compartment (pericentromeric/laminar/nucleolar versus non-pericentromeric and nucleolus-excluded) and on dependency (flat versus broad), and neither ever measured at the KMT2A locus

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

  writes H3K9me3; the H3K9me3-specific methyltransferase of the pair, non-pericentromeric and nucleolus-excluded

• regulates →HOXA9 — required for survival of established MLL-rearranged leukemia, and dispensable for starting it

  PAF1c-SETDB1 raises promoter H3K9me3 at Hoxa9 and reduces its transcription in mouse MLL-AF9 cells; higher SETDB1 tracks with lower HOXA9 in human AML

• regulates →MEIS1 — rate-limiting for MLL leukemia stem cells, a surviving co-dependency, and embryonic-lethal when removed

  PAF1c-SETDB1 raises promoter H3K9me3 at Meis1 and reduces its transcription in mouse MLL-AF9 cells

• ← recruitsCDC73 / parafibromin — the PAF1C subunit that was genetically tested, and a second tumour suppressor required by the fusion

  PAF1c interacts with SETDB1 in MLL-AF9 cells; the CDC73_3YF mutant stabilises the interaction and cannot support AML growth

• expressed in →Fetal liver haematopoietic stem and progenitor cell — the leading candidate cell of origin for t(4;11) infant ALL

  required in mouse fetal liver HSPCs: Setdb1 deletion compromises stem-cell function, enhances myeloerythroid differentiation and impairs lymphoid development via cryptic-enhancer activation

• ← bindsTRIM28 / KAP1 / TIF1beta (Q13263) - the KRAB-ZFP corepressor scaffold in the pan-MLL-fusion core, with the weakest index-fusion p-value but a leukaemic role in another fusion family

  TRIM28/KAP1 protects SETDB1 from degradation at telomeres, maintaining the H3K9me3 state; and the two co-occupy ZNF 3' exons with ZNF274 and ATRX

• ← part ofATRX - 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 forms a complex with SETDB1, TRIM28 and ZNF274 co-occupying the 3' exons of zinc-finger genes, the one uncontroversial genomic address of this writer

• ← recruitsCTCF - named in the id of an existing entry in this graph and having no entry of its own, and the protein whose binding sites break preferentially in KMT2A-rearranged patients

  CTCF recruits SETDB1 alongside SUV39H1, HP1-gamma, KAP1 and KDM5A to double-strand breaks (U2OS/HEK293T)

• ← regulatesHIRA - the chaperone that puts new H3.3 into transcribed gene bodies, and therefore the machine that runs this graph's clearance clock

  HIRA knockdown in K562 raises H3K9me3 and HP1-alpha through SETDB1, compacting chromatin toward the nuclear periphery

• ← recruitsCBX5 / 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

  the CHAMP1-POGZ-HP1-alpha complex binds and recruits SETDB1 to heterochromatin and is required for homology-directed repair there

• related to →H3K9me1 - 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

  candidate explanation for the replicate-consistent H3K9me3 rise over the KMT2A BCR under BOTH single knockdowns in GSE210480, which is the wrong shape for a KDM3B-G9a balance - Q108 named SETDB1 redistribution as one of three candidates

• ← 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

  measured-not-analysed rather than never-measured: three K562 ChIP-seq experiments existed and nobody had read them at this locus

• ← testsRUN: ten ENCODE peak sets and fourteen signal tracks read at the KMT2A locus in two blood cells - not one called peak for SETDB1, CBX5, CBX1, CBX3 or TRIM28 anywhere in the gene, while G9a/EHMT2 and TRIM28 both sit on the KMT2A PROMOTER and neither touches the breakpoint cluster region

  reads three K562 SETDB1 peak sets and five signal tracks at the KMT2A locus: zero called peaks in the gene or within 50 kb, with the ZNF274 gene-body positive control passing

• ← 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)

  the first alternative writer - and it has no called peak at this locus in K562

• ← testsDAXX and ATRX are absent from the only MLL-fusion AP-MS interactome - and PML is in it against all seven baits, alone, without a single one of its other body components

  answers gene-trim28's question: SETDB1 is NOT in the 960-protein network, so TRIM28 is there as a lone scaffold rather than a TRIM28-SETDB1 module

• supports →BRCA1 (P38398, 1,863 aa) - named in 19 entries of this graph and never written: the HR mediator that CTCF and the H3K9 machinery are now reported to license at a break, and the only cascade member with a human therapy-related-leukaemia signal after topoisomerase II therapy

  second H3K9 writer in the same CTCF-recruited assembly