KANSL1 - the NSL scaffold, and the protein through which WDR5 binding to NSL and to MLL/COMPASS is mutually exclusive

This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.

• KANSL1 has no KMT2A selectivity in any DepMap cut run here, and the published MOF requirement spans MLL-AF9 and NUP98-HOXA9 leukaemogenesis alike - so an NSL-directed agent would be a broad myeloid-leukaemia agent, not a KMT2A-selective one.
• If NSL and MLL/COMPASS compete for a limited WDR5 pool, then inhibiting NSL could RELEASE WDR5 to SET1/MLL complexes, which is the opposite of the desired direction in a disease that depends on a wild-type KMT2A complex. This is a compensation risk that follows directly from the structural result.
• KANSL1 is annotated to the mitochondrion, kinetochore and spindle pole as well as the nucleus. A degrader would carry mitotic and metabolic liabilities that a chromatin-only mental model would not predict.
• KANSL1 haploinsufficiency causes Koolen-de Vries syndrome [E9], so constitutive partial loss of this protein has a named human developmental phenotype - a relevant caution for any chronic systemic inhibitor in a paediatric population, though not a direct prediction about transient dosing.
• ESSENTIAL-FUNCTION TOXICITY — KANSL1 has the clearest human loss-of-function phenotype of any gene in this tranche, and it is bad: roughly half-normal dosage produces Koolen-de Vries syndrome, a named neurodevelopmental disorder. That is a dosage phenotype, so no amount of potency or target selectivity answers it, and the population this graph treats is infants whose brains are still being built. Any KANSL1-lowering strategy has to begin by answering this.

1. If WDR5's NSL and MLL/COMPASS interactions are mutually exclusive, does depleting KANSL1 increase WDR5 availability to SET1/MLL complexes in a leukaemia cell, and does that change H3K4me3 at KMT2A::AFF1 target genes? This has never been measured and is the experiment this entry exists to motivate.
2. Which NSL subunit makes the contact with NUP98 fusion proteins? The published result is at complex level, and the answer determines whether a subunit-selective intervention is even conceivable.
3. Does KMT2A::AFF1 interact with NSL at all? Five NUP98 fusions do; no query run in this beat found a report either way for a KMT2A fusion, so this is an untested absence rather than a negative result.
4. Is H4K5/K8 acetylation - the NSL-specific output, as distinct from the MSL-specific H4K16ac - altered at HOXA9 and MEIS1 in KMT2A-rearranged cells? The graph currently reasons about MOF through H4K16ac, which the composition paper says is the wrong mark for NSL.
5. The mitochondrial-quality-control defect at KANSL1 half-dosage has been shown in neurons in two species. Is it neuron-specific? If it is general, a haematopoietic cell at half dosage should show it too, and the complete absence of any KANSL1 haematopoietic phenotype in the literature becomes a real question rather than a gap in attention. Kansl1+/- mouse marrow already exists.
6. This graph places KANSL1 in the fusion interactome at NSL-complex level while every cell-type and cell-state fact about KANSL1 is neuronal and every haematopoietic fact about the NSL complex belongs to KAT8. What would it take to show that KANSL1 itself does anything in a blast? A KANSL1-selective degrader with an NSL-integrity readout is the minimum.

1. E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   The NSL complex is composed of nine subunits; two of them, WDR5 and HCF1, are shared with members of the MLL/SET family of H3K4 methyltransferase complexes and a third, MCRS1, is shared with the human INO80 remodelling complex. Assembly of MOF into MSL versus NSL controls its substrate specificity: MSL-associated MOF acetylates nucleosomal H4 almost exclusively on K16, whereas NSL-associated MOF has relaxed specificity and also acetylates H4 on K5 and K8.

   Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex · Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC · Journal of Biological Chemistry 285(7):4268-72 2010
   PMID 20018852DOI
   ▸What this evidence cannot show

   Abstract fetched from PubMed and read on 2026-09-19; full text not read, every identifier copied from that fetched record. Proteomic purification through multiple candidate subunits in human cells; substrate specificity measured on nucleosomal substrates in vitro, so the in vivo mark distribution may differ. **The paper calls WDR5 and HCF1 'shared', which a later structural study contradicts in the sense of simultaneous engagement (see E2)** - this entry reports the composition from here and does not adopt the word 'shared' in its own voice.

   ▸Evidence that argues against this (1)

   • The claim that WDR5 and HCF1 are shared subunits is contradicted as a statement about simultaneous membership by the KANSL1/WDR5/KANSL2 structure, which shows WDR5's NSL and MLL/COMPASS interactions are mutually exclusive. Composition by proteomics cannot distinguish 'present in both complexes' from 'present in both at once'. Dias J et al. 2014
2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   KANSL1 acts as a scaffold interacting with four other NSL subunits including WDR5, which in turn binds KANSL2; the KANSL1/WDR5/KANSL2 structure shows WDR5 is recruited via conserved linear motifs of KANSL1 and KANSL2; structure-based KANSL1 mutants in transgenic flies show the KANSL1-WDR5 interaction is required for proper NSL assembly, efficient recruitment of NSL to target promoters and fly viability; and the interactions of WDR5 with the MOF-containing NSL complex and with MLL/COMPASS histone methyltransferase complexes are mutually exclusive.

   Structural analysis of the KANSL1/WDR5/KANSL2 complex reveals that WDR5 is required for efficient assembly and chromatin targeting of the NSL complex · Dias J, Van Nguyen N, Georgiev P, Gaub A, Brettschneider J, Cusack S, Kadlec J, Akhtar A · Genes & Development 28(9):929-42 2014
   PMID 24788516DOI
   ▸What this evidence cannot show

   Abstract fetched from PubMed and read on 2026-09-19; full text not read, identifiers copied from that fetched record. Crystallography plus Drosophila genetics; **the in vivo requirement is established in flies, not in mammalian cells, and certainly not in leukaemia**. 'Mutually exclusive' is an inference from the structural overlap of binding sites on WDR5 together with binding data; this entry did not read the competition experiments themselves. The functional consequence for a KMT2A-rearranged cell is a prediction of this graph, not a finding of this paper.

   ▸Evidence that argues against this (1)

   • An earlier proteomic study describes WDR5 and HCF1 as subunits shared between NSL and MLL/SET complexes and reasons from that sharing to functional crosstalk. The two accounts are reconcilable - a protein can belong to two complexes without being in both simultaneously - but the reconciliation appears in neither paper, and any diagram placing WDR5 inside NSL and inside the KMT2A complex at the same time is inconsistent with this structure. Cai Y et al. 2010
3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   Depletion of the NSL subunits hMOF or NSL1 significantly reduced both H4K16ac and H3K4me2 near the ANKRD2 transcription start site, whereas depletion of RbBP5, a core component of MLL/SET complexes, reduced H3K4me2 only and not H4K16ac - consistent with NSL acting upstream of MLL/SET to regulate H3K4me2 at certain promoters. A set of genes including ANKRD2 was affected by knockdown of both NSL and MLL/SET subunits.

   Crosstalk between NSL histone acetyltransferase and MLL/SET complexes: NSL complex functions in promoting histone H3K4 di-methylation activity by MLL/SET complexes · Zhao X, Su J, Wang F, Liu D, Ding J, Yang Y, Conaway JW, Conaway RC, Cao L, Wu D, Wu M, Cai Y, Jin J · PLoS Genetics 9(11):e1003940 2013
   PMID 24244196DOI
   ▸What this evidence cannot show

   Abstract fetched from PubMed and read on 2026-09-19; full text not read, identifiers copied from that fetched record. **The exemplar locus is ANKRD2, a skeletal-muscle ankyrin-repeat gene, in human cell lines - not a HOXA locus and not a haematopoietic system.** Knockdown rather than acute degradation, so secondary effects are not excluded. The ordering claim (NSL upstream of MLL/SET) rests on an asymmetry in two knockdowns at one promoter, which is suggestive rather than decisive. 'NSL1' in this paper means KANSL1, not the kinetochore protein of the same name.

   ▸Evidence that argues against this (1)

   • The generalisability of a single-promoter epistasis result is the obvious weakness, and the same laboratory's earlier composition paper shows NSL and MLL/SET share components whose depletion would perturb both complexes - so 'NSL upstream of MLL/SET' and 'the two complexes compete for a shared limiting component' predict similar knockdown asymmetries and are not distinguished by this experiment. Dias J et al. 2014
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   NUP98 fusion proteins including NUP98-HOXA9, NUP98-HOXD13, NUP98-NSD1, NUP98-PHF23 and NUP98-TOP1 physically interact with MLL1 and with the non-specific lethal (NSL) histone-modifying complex; ChIP-seq shows NUP98-HOXA9 and MLL1 co-localise on chromatin at HOX gene promoter regions; MLL1 is required for the proliferation of NUP98-HOXA9 cells in vitro and in vivo; and inactivation of MLL1 decreases expression of genes bound by NUP98-HOXA9 and MLL1 and reverses a gene expression signature found in NUP98-rearranged human leukaemias.

   NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis · Xu H, Valerio DG, Eisold ME, Sinha A, Koche RP, Hu W, Chen CW, Chu SH, Brien GL, Park CY, Hsieh JJ, Ernst P, Armstrong SA · Cancer Cell 30(6):863-878 2016
   PMID 27889185DOI
   ▸What this evidence cannot show

   Abstract fetched from PubMed and read on 2026-09-19; full text not read, every identifier copied from that fetched record. **The fusions studied contain no KMT2A**; this is evidence that a second fusion family runs through the wild-type MLL1 complex, not evidence about KMT2A::AFF1. Models are murine transformation and xenograft systems plus human NUP98-rearranged expression signatures; no primary paediatric patient material is described in the abstract. 'Physically interact with the NSL complex' is stated at complex level and the abstract does not name which NSL subunit makes the contact.

   ▸Evidence that argues against this (1)

   • The complementary result from the same group is that MOF's catalytic activity is required for MLL-AF9 leukaemogenesis AND that Mof inactivation suppresses leukaemia development in an NUP98-HOXA9 model - so the MOF/NSL requirement spans both fusion families. That breadth is exactly what argues against NSL being a KMT2A-specific vulnerability, and it is consistent with KANSL1 showing no KMT2A selectivity in DepMap. Valerio DG et al. 2017
5. E5moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   In the genome-wide KMT2A-rearranged selectivity scan of 17,728 genes, KANSL1 has a pan-essentiality of -0.7402 across 1,208 lines and a KMT2A-rearranged selectivity difference of +0.0685 (KMT2A-rearranged mean -0.681 against other-leukaemia mean -0.7494), ranking 15,913 (89.762nd percentile). Other NSL-associated genes: KANSL2 +0.2265 rank 17,631; KANSL3 +0.0371 rank 13,630; KAT8 +0.0041 rank 9,683; MCRS1 +0.0139 rank 10,971; PHF20 +0.0339 rank 13,286; OGT -0.0829 rank 1,634.

   Genome-wide KMT2A-rearranged selectivity scan, 17,728 genes (DepMap Chronos via Open Targets) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-kmt2a-selective-scan-full 2026
   ▸What this evidence cannot show

   Rows read out of analyses/depmap-kmt2a-selective-scan-full/results.json on 2026-09-19 in a scripted pass; no number typed from recall. Eleven KMT2A-rearranged against 43 other leukaemia lines, AML-heavy, none infant-derived. KANSL1's pan-essentiality of -0.74 is moderate, so floor compression is less severe here than for FACT, but the difference of +0.0685 is well inside the range where nothing should be concluded.

   ▸Evidence that argues against this (1)

   • Seven of the eight NSL-associated genes fall on the anti-selective side of the median, which would be a striking pattern if the NSL requirement were KMT2A-specific and is exactly what is expected if NSL is general machinery required comparably by all leukaemia lines. The published MOF result - required for MLL-AF9 AND for NUP98-HOXA9 leukaemogenesis - predicts precisely this lack of differential. Valerio DG et al. 2017
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   On the lineage-split run for this beat, KANSL1 shows no KMT2A-rearranged requirement in either lineage half: myeloid raw mean gene effect -0.688 (z +0.16 in other-leukaemia SDs), B-lineage raw mean -0.624 (z +0.36). OCI-AML3 sits at z -0.02 and U-937 at z -1.22. KAT8 in the same run: myeloid z -0.13, B-lineage z +0.24, OCI-AML3 z +1.41.

   Interactome round 5 panel, lineage-split DepMap dependency (FACT, NSL, MSL, COMPASS remainder, Mediator) · Broad Institute DepMap / Open Targets Platform; analyses/depmap-interactome5-lineage-split 2026
   ▸What this evidence cannot show

   Rows read from analyses/depmap-interactome5-lineage-split/results.json on 2026-09-19. Six myeloid and four B-lineage index lines, so a single line moves a mean; the split is by lineage LABEL, not expression signature. The U-937 value of z -1.22 is a single line carrying a PICALM::MLLT10 fusion and is reported for reference only; one-line z values are not dependency claims.

   ▸Evidence that argues against this (1)

   • A viability screen is a poor instrument for NSL specifically, because the published leukaemia result about this complex concerns MOF catalytic activity in transformation and leukaemia initiation in mice rather than proliferation of established human lines - and a catalytic-dead rescue was needed there to make the point. A null z in DepMap does not contradict that result. Valerio DG et al. 2017
7. E7established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   UniProtKB Q7Z3B3 (KANL1_HUMAN, KAT8 regulatory NSL complex subunit 1) is 1,105 aa with synonyms CENP-36, KIAA1267, MSL1V1 and NSL1; it is annotated to nucleus, kinetochore, mitochondrion and spindle pole; and it carries a PEHE domain at 884-1035, a region required for activation of KAT8 histone acetyltransferase activity at 850-882, a region interacting with the KAT8 HAT domain at 910-928, and a coiled coil at 283-314. Two PDB entries exist, 4CY1 and 4CY2.

   UniProtKB Q7Z3B3 (KANL1_HUMAN), KAT8 regulatory NSL complex subunit 1 · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
   ▸What this evidence cannot show

   Record fetched 2026-09-19 via UniProt REST with gene_exact:KANSL1 AND organism_id:9606 AND reviewed:true; **primary gene name read back as KANSL1 and length 1,105 confirmed from the same fetched record**, per the standing accession rule. One reviewed hit. The mitochondrial and kinetochore annotations are UniProt curation from separate literatures not read for this entry and are reported as annotations rather than asserted as facts about leukaemia cells.

   ▸Evidence that argues against this (1)

   • The UniProt synonym NSL1 collides with an unrelated kinetochore gene of the same symbol, and KANSL1 is itself annotated to the kinetochore - which makes this an alias trap that cannot be resolved by localisation and must be resolved by reading titles. One of the four records in this beat's KANSL1 query is exactly that false positive. NCBI PubMed, queried 2026-09-19 2026
8. E8moderate confidence 3 of 5: One strong study, or several smaller consistent ones.database

   As of 2026-09-19 PubMed returns 4 records for '(MLL OR KMT2A) AND (KANSL1 OR KIAA1267 OR MSL1v1 OR NSL1)', 3 for '(MLL OR KMT2A) AND KANSL1', 4 for '(MLL OR KMT2A) AND ("NSL complex" OR "non-specific lethal")' and 8 for '("NSL complex" OR KANSL1 OR KANSL2 OR KANSL3) AND (leukemia OR leukaemia)'. Title-checking the 4-record alias query leaves 2 relevant papers - the KANSL1/WDR5/KANSL2 structure and the NSL-MLL/SET crosstalk study; the other two are an IDH1/2-JARID1C-UTX metabolic review and a kinetochore Blinkin interaction-mapping paper matched on the unrelated NSL1 symbol. The 8-record leukaemia query yields no additional functional paper: it returns a KANSL1::ARL17A case report, a KANSL1-MTCP1 fusion case, a relapsed-AML genomics paper, a T-LBL fusion-transcript survey and a Down-syndrome myeloid mutation landscape.

   PubMed E-utilities esearch record counts for the NSL complex subunits against KMT2A, MLL and leukaemia, run for interactome round 5 · NCBI PubMed, queried 2026-09-19 2026
   ▸What this evidence cannot show

   Counts from the esearch `count` field, queried 2026-09-19, with **every record in each counted query title-checked individually**. Symbol set: KANSL1, KIAA1267, MSL1v1, NSL1, KANSL2, KANSL3, plus the phrases 'NSL complex' and 'non-specific lethal'. The alias NSL1 inflates and was the reason title-checking was required. Not searched: 'KAT8 regulatory NSL complex subunit' as a phrase.

   ▸Evidence that argues against this (1)

   • The NUP98 paper that provides the strongest leukaemia link for NSL does not appear in the KANSL1 alias query at all - it is found only through the phrase queries - which demonstrates that a subunit-symbol enumeration alone would have reported NSL as having no leukaemia literature and been wrong. Complex-name phrases had to be searched alongside gene symbols. Xu H et al. 2016
9. E9established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   KANSL1 haploinsufficiency causes Koolen-de Vries syndrome, a recognised human developmental disorder with a described adult phenotype.

   Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome · Amenta S, Frangella S, Marangi G, Lattante S, Ricciardi S, Doronzio PN, Orteschi D, Veredice C · Journal of Medical Genetics 59:189-195 2022
   PMID 33361104DOI
   ▸What this evidence cannot show

   Title, journal, volume, pages, year, authors and DOI were read from the PubMed esummary record fetched on 2026-09-19; the abstract and full text were NOT read in this session, so this citation is used only for the existence and name of the syndrome, which its title states. It is cited here for a bite-back argument about systemic inhibition and for nothing mechanistic.

   ▸Evidence that argues against this (1)

   • A germline haploinsufficiency phenotype bounds the tolerability of constitutive 50% loss across development; it does not directly predict the tolerability of transient pharmacological inhibition in an older child, and treating it as if it did would overstate the argument. UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
10. E10strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    The only cell type in which KANSL1 has a documented cell-state phenotype is the neuron: hiPSC-derived neurons from Koolen-de Vries syndrome patients, who carry KANSL1 haploinsufficiency, show reduced network burst rates and increased variability in burst rhythmicity on microelectrode arrays together with impaired mitochondrial function and reduced synaptic density, and the antioxidant phloretin improves the network phenotype, reduces reactive oxygen species and rescues synaptic density across patient lines.

    Integrative transcriptomics and electrophysiological profiling of hiPSC-derived neurons identifies novel druggable pathways in Koolen-de Vries Syndrome. · Verboven AHA, Puvogel S, Latour BL, Kolsters N, Lewerissa EI, Mijdam R, Dyke E, Duineveld D, Zoodsma M, Claassen WJJ, Oudakker A, Schoenmaker C, Koolen DA, de Vries BBA, 't Hoen PAC, Linda K, Nadif Kasri N · Mol Psychiatry 2026
    PMID 41680331DOI
    ▸What this evidence cannot show

    Human iPSC-derived neurons on microelectrode arrays - a reductionist model of a cortical network. The drug nomination is a computational LINCS signature screen with ten candidates triaged. No haematopoietic, leukaemic or KMT2A-rearranged system anywhere in the paper. Read: abstract only. Recorded here as the human loss-of-function phenotype that constrains any KANSL1-lowering strategy, not as leukaemia biology.

    ▸Evidence that argues against this (1)

    • The murine work on the same haploinsufficiency attributes the neuronal defect to failed autophagosome-lysosome fusion through transcriptional control of STX17 and rescues it with 13-cis retinoic acid, not with an antioxidant. Two models of one phenotype, converging on damaged-mitochondria handling and disagreeing on the route, with neither testing the other. Li T et al. 2022
11. E11moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    The haematopoietic cell-type biology of the NSL complex belongs to KAT8/MOF and not to KANSL1, and must not be transferred: MOF and H4K16ac levels are heterogeneous among haematopoietic stem cells and influence their proliferation capacity, with a CD93-positive HSC subpopulation expanded and proliferatively advantaged in Mof heterozygous animals in a state the authors describe as reminiscent of premalignancy, and low MOF with high CD93 correlating with poor survival in leukaemia.

    Differential H4K16ac levels ensure a balance between quiescence and activation in hematopoietic stem cells. · Pessoa Rodrigues C, Akhtar A · Sci Adv 2021
    PMID 34362741DOI
    ▸What this evidence cannot show

    This is a MOF/KAT8 result, NOT a KANSL1 result, and it is recorded on this entry only to mark what the complex-level literature does and does not license. Mouse. Read: abstract only. No KANSL1 perturbation appears in it.

    ▸Evidence that argues against this (1)

    • A second MOF study points at a different cell-fate axis again - MOF timing and dosage acting as a rheostat on a MOF-RUNX1-GFI1B feedforward network for erythroid fate commitment, with Mof haploinsufficiency causing accumulation of a transient HSC population. So even at the level of the correct subunit, MOF's haematopoietic role is described as quiescence-versus-activation in one paper and erythroid fate commitment in another. Borrowing either for KANSL1 would import an unsettled result into the wrong gene. Pessoa Rodrigues C et al. 2020

• part of →NSL complex - the MOF assembly that five NUP98 fusions bind alongside MLL1, and that competes with MLL/COMPASS for WDR5

  Scaffold subunit of the nine-subunit NSL complex.

• binds →WDR5 — the partner that is not a partner: it binds the half of KMT2A the fusion throws away

  KANSL1 recruits WDR5 via a conserved linear motif; this interaction is mutually exclusive with WDR5's binding to MLL/COMPASS complexes.

• binds →KAT8 (MOF) — a genuine KMT2A partner that binds the half of KMT2A the fusion discards

  KANSL1 activates KAT8/MOF; activation region aa 850-882 and HAT-domain contact aa 910-928.

• related to →KMT2A / MLL1 — the gene that breaks

  NSL depletion lowers H3K4me2 as well as H4K16ac at a shared promoter, placing NSL upstream of MLL/SET complexes.

• binds →KANSL2 - the second NSL subunit in the WDR5 structure, with one leukaemia record and a dependency profile that is the mirror image of a selective target

  KANSL1 and KANSL2 both contribute conserved linear motifs to the WDR5 subcomplex.

• related to →HCFC1 (HCF-1) — a founding member of the wild-type KMT2A complex that the fusion cannot bind

  HCF1 is reported as a component of both NSL and MLL/SET complexes.

• ← bindsKANSL2 - the second NSL subunit in the WDR5 structure, with one leukaemia record and a dependency profile that is the mirror image of a selective target

  Both contribute WDR5-binding motifs to the same subcomplex.

• ← part ofNSL complex - the MOF assembly that five NUP98 fusions bind alongside MLL1, and that competes with MLL/COMPASS for WDR5

  KANSL1 is the NSL scaffold.

• ← related toMSL1 - the MSL scaffold that carries MOF and MSL2 to HOXA9 and MEIS1, with zero records against KMT2A and a mapped, drawable domain architecture

  Parallel scaffolds: both use a PEHE domain to hold MOF, and the complex they build determines whether MOF writes H4K16ac alone or also H4K5ac and H4K8ac.

• ← related toWDR5 is partitioned, not shared: NSL and SET1/MLL complexes compete for one pool, so perturbing NSL changes how much WDR5 reaches the wild-type KMT2A complex the fusion depends on

  The NSL scaffold whose conserved linear motif recruits WDR5, and the protein the deciding experiment degrades.

• ← related toDoes WDR5 move between complexes? An acute KANSL1 degron with WDR5 co-IP, WDR5 CUT&RUN and H4K5/K8/K16ac readout in a KMT2A-rearranged line

  KANSL1 is the degron-tagged protein.

• ← related toKAT8/MOF is not only a chromatin enzyme: a measured mitochondrial pool binds mtDNA, and the chromatin address depends on which complex it is in

  NSL partners co-fractionate with MOF into mitochondria; mtDNA binding is KANSL3-dependent

• ← related toH4K16ac - the one mark rule 80 actually rescued in this beat: elevated at MLL-AF9 targets in a supplementary figure, and the reason MLL1's own enzyme turns out to be dispensable

  KAT8 writes this mark inside the NSL complex

• regulates →Neuron - the off-target cell type that defines what KANSL1 loss costs a human being

  KANSL1 haploinsufficiency (Koolen-de Vries syndrome) impairs neuronal network bursting, mitochondrial function and synaptic density in patient hiPSC-derived neurons, and mitophagy and neuronal function in Kansl1+/- mice; the human loss-of-function phenotype that constrains any KANSL1-lowering strategy