Oncofusion

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Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q37-histone-chaperones

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

also called HIRA · TUPLE1 · DGCR1 · HIR · P54198 · histone cell cycle regulator

HIRA slots fresh copies of a special histone protein into genes while they are being read, without waiting for the cell to divide. That matters here because the chemical tag this project's main drug target writes can only be lost when the histone carrying it is swapped out, and HIRA is the swapper at exactly the genes a KMT2A fusion forces open.

The same thing, for a scientist

HIRA (P54198, 1,017 aa) is the replication-independent H3.3 chaperone. With UBN1, CABIN1 and ASF1A it forms the HUCA complex [E2] and is required for H3.3 enrichment at active and repressed genes, but **not** at telomeres, where ATRX/DAXX act instead [E1]. This graph's H3K79 argument (`mechanism-h3k79-turnover-and-dilution`) says the mark is lost only by histone replacement; HIRA is the replication-independent half of that replacement. **The premise this beat was dispatched on - that HIRA is absent from the leukaemia literature - is half wrong.** `HIRA AND (MLL OR KMT2A OR "mixed lineage leukemia")` returns **0** including the aliases TUPLE1 and DGCR1 [E6], so the KMT2A intersection is genuinely empty. But `HIRA AND leukemia` returns 37 and includes a 2026 mechanistic paper in CML: HIRA is over-expressed in CML patient samples, and HIRA knockdown in K562 compacts chromatin, raises H3K9me3 and HP1-alpha through SETDB1, and **reduces BCR::ABL1 expression** [E3]. HIRA is a leukaemia gene; it is not a KMT2A gene. **And it is probably not a dependency here.** In the 11 KMT2A-rearranged DepMap lines HIRA's difference from other leukaemia lines is **-0.082** at a pan-essentiality of **-0.81**, and the sign flips across the lineage split: **-0.147 in the myeloid half, +0.032 in the lymphoid half** [E7]. The index disease of this graph is lymphoid.

Go deeper
What HIRA does, and what it demonstrably does not do

Two purified complexes, one for each H3 variant: CAF-1 carries H3.1 and deposits it coupled to DNA synthesis; HIRA carries H3.3 and deposits it independent of DNA synthesis 4. Each complex holds one H3-H4 dimer, not a tetramer, which is why ASF1 can hand off to both routes.

The division of labour within H3.3 is the part that matters for this beat. Endogenously tagged H3.3 in mouse ES and neural precursor cells shows HIRA is required for H3.3 at active and repressed genes and is not required at telomeres or at many transcription-factor binding sites, where ATRX and DAXX take over 1. So:

routechaperonewherereplication
gene bodies, promoters, regulatory elementsHIRA/UBN1/CABIN1 + ASF1Atranscribed and poised chromatinindependent
telomeres, pericentric and ERV heterochromatinATRX/DAXXH3K9me3 domainsindependent
bulk chromatin behind the forkCAF-1 (CHAF1A/B/RBBP4) + ASF1everywhere, S phasecoupled

A fusion that forces elongation acts on row 1. That is the entire reason this entry leads the beat.

The blood phenotype is contested, and the contest is not a detail

Two papers one year apart reach opposite conclusions about whether HIRA is needed by adult haematopoietic stem cells.

  • Required. Conditional Hira deletion rapidly depletes adult HSCs while differentiated cells are largely unaffected; H3.3 occupies a subset of polycomb-repressed chromatin that needs HIRA to stay inaccessible, and losing it de-represses erythroid genes 5.
  • Not required. "H3.3, but not its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors" 8.

And a third, in fetal liver - the compartment this graph believes infant KMT2A::AFF1 arises in - states flatly that HIRA was dispensable in fetal haematopoiesis and that ASF1B, not HIRA, determines H3.3 enrichment at erythroid genes 9.

This is not noise to be averaged. It says the H3.3 requirement in blood can be met without HIRA, which is exactly what a redundant, buffered deposition network predicts, and it is the single strongest argument against making HIRA an intervention target in this disease. It also means an experiment that deletes HIRA and sees nothing has not tested H3.3.

Subnuclear: HIRA goes to PML bodies, and needs Sp100A to get there

HIRA, UBN1 and ASF1A fail to localise to PML nuclear bodies in Sp100-knockout keratinocytes, even after interferon; the Sp100A isoform is the driver and its SUMO-interacting motif is required 10. The authors are explicit that this recruitment is not needed for immediate interferon signalling and is instead a candidate mechanism for epigenetic memory by delayed H3.3 incorporation.

This graph already carries protein-pml-domains and a subnuclear beat, and gene-daxx argues the PML connection from the ATRX/DAXX side. Both H3.3 routes converge on PML bodies from different directions, which is a stronger reason to look at PML here than either route alone. It remains keratinocyte and heterologous-system evidence with no leukaemic data.

Facts and figures
uniprotP54198
gene symbolHIRA
length AA1017
complexprotein-huca-complex
depositsprotein-histone-h3-3
deposition modereplication-independent
genomic targetstranscribed gene bodies, promoters, cis-regulatory elements; NOT telomeres
kmt2a literature records0
subnuclear localizationPML nuclear bodies (Sp100A-dependent, SIM-dependent) and senescence-associated heterochromatin foci; in leukaemia cells the only spatial measurement is of CHROMATIN moving to the nuclear periphery when HIRA is lost, not of HIRA itself.
shown for fusionNO. HIRA[tiab] AND (KMT2A[tiab] OR MLL[tiab]) returns ZERO records (PubMed esearch, 2026-09-21), consistent with the kmt2a_literature_records: 0 already on this entry; HIRA[tiab] AND (leukemia OR leukaemia)[tiab] returns 11, of which the only mechanistic leukaemia paper is in K562, a BCR::ABL1 CML line. No HIRA imaging, fractionation or PML-body assay has been performed in any KMT2A-rearranged cell. Zero in titles and abstracts; supporting figures not searched.
depmap
index_mean-0.830index_mean: -0.8304pan_essentiality-0.814pan_essentiality: -0.8139other_leukaemia_mean-0.749other_leukaemia_mean: -0.7486myeloid_difference-0.147myeloid_difference: -0.1467difference-0.082difference: -0.0818lymphoid_difference0.032lymphoid_difference: 0.0315n_index_lymphoid4.000n_index_lymphoid: 4n_index_myeloid7.000n_index_myeloid: 7n_index11.0n_index: 11
depmap — the numbers behind the chart
{
  "index_mean": -0.8304,
  "other_leukaemia_mean": -0.7486,
  "difference": -0.0818,
  "pan_essentiality": -0.8139,
  "n_index": 11,
  "myeloid_difference": -0.1467,
  "lymphoid_difference": 0.0315,
  "n_index_myeloid": 7,
  "n_index_lymphoid": 4
}
localization
{
  "subcellular": "Nucleus. HIRA is a nuclear H3.3 chaperone; no cytoplasmic pool is measured in any source read for this beat, and the entry records the nuclear assignment from imaging rather than from a UniProt 'by similarity' line. UniProt P54198 was used only as a pointer to the primary imaging literature and no localisation string was taken from it.",
  "subnuclear": "PML nuclear bodies, and senescence-associated heterochromatin foci (SAHF). In human keratinocytes HIRA and its complex partners UBN1 and ASF1A localise to PML nuclear bodies, and that localisation is abolished by Sp100 knockout and driven specifically by the Sp100A isoform through its SUMO-interacting motif. In senescing human fibroblasts HIRA transits through PML bodies as a step in SAHF formation. A third, distinct subnuclear readout exists in leukaemia: in K562 chronic myeloid leukaemia cells HIRA knockdown compacts chromatin and shifts its spatial distribution toward the NUCLEAR PERIPHERY, measured by FRAP and FLIM-FRET - a chromatin-architecture readout, not a HIRA address.",
  "how_shown": "immunofluorescence colocalisation with PML in CRISPR Sp100-knockout normal human keratinocytes with isoform add-back and SIM mutant panel (PMID 41093075); IF/SAHF assays in human diploid fibroblasts (PMID 17242198); FRAP and FLIM-FRET imaging of chromatin in HIRA-knockdown K562 cells (PMID 42055326)",
  "systems": "human keratinocytes; human diploid fibroblasts; K562 (BCR::ABL1 CML) - none of them KMT2A-rearranged",
  "node": "localization-pml-nuclear-bodies-pmlrara"
}
localization counted absence
{
  "query": "HIRA[tiab] AND (KMT2A[tiab] OR MLL[tiab])",
  "records": 0,
  "operand_controls": {
    "HIRA[tiab] AND (leukemia[tiab] OR leukaemia[tiab])": 11,
    "HIRA[tiab] AND (nucleolus OR nucleolar OR \"PML nuclear bodies\" OR \"nuclear bodies\" OR heterochromatin)[tiab]": 45
  },
  "date": "2026-09-21",
  "tool": "PubMed E-utilities esearch",
  "bound": "zero in titles and abstracts; supporting figures not searched"
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.8304,
  "chronos_mean_other_leukaemia": -0.7486,
  "difference": -0.0818,
  "pan_essentiality_all_lines": -0.8139,
  "selectivity_rank": 1682,
  "rank_denominator": 17728,
  "provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
  "how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}
How this could bite us back
  • HIRA packages the genome of every transcribing cell. Its DepMap pan-essentiality of -0.81 across 1,208 lines says a general block on HIRA has no obvious therapeutic window, and the selectivity that would create one is absent (-0.082, and reversed in the lymphoid half).
  • Conditional Hira deletion rapidly depletes adult mouse HSCs while sparing differentiated cells - the exact inverse of the selectivity a leukaemia-stem-cell-directed therapy needs, and a direct prediction of marrow failure.
  • If ASF1B can deposit H3.3 without HIRA in haematopoietic cells, then inhibiting HIRA is buffered by design and an apparently clean HIRA knockout that shows no phenotype will be read as 'H3.3 does not matter here' when it shows nothing of the kind.
  • Slowing H3.3 deposition would slow the clearance of H3K79 methylation, not speed it. Anything that reduces nucleosome turnover is predicted to make a DOT1L inhibitor work more slowly, so a chaperone inhibitor is an antagonist of this graph's own drug hypothesis rather than a partner for it.
Still open
  1. Does KMT2A::AFF1 occupancy overlap HIRA-dependent H3.3 deposition at its target genes? Nobody has done the overlap and both datasets are ChIP-scale.
  2. Adjudicate the HSC contradiction: does adult HSC self-renewal require HIRA (PMID 34242617) or not (PMID 34961794)? The cheapest discriminator is whether ASF1B can carry H3.3 in the absence of HIRA in that compartment, which the fetal-liver paper says it can.
  3. If HIRA is dispensable for H3.3 in blood, is the gene-body H3.3 route in a KMT2A-rearranged blast run by ASF1B rather than HIRA - and does that change which gene you would perturb to move the clearance clock?
  4. Both H3.3 routes reach PML bodies (HIRA via Sp100A, ATRX/DAXX via PML itself). Does a KMT2A fusion occupy or perturb PML-associated domains at all?
  5. Does HIRA enter PML nuclear bodies in a KMT2A-rearranged blast, and does a menin inhibitor change that? The Sp100A/SIM dependency gives a clean genetic handle (Sp100 knockout abolishes it) and the experiment has never been attempted outside keratinocytes and fibroblasts.
Every source behind this entry (14)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    With endogenously tagged H3.3 in mouse embryonic stem and neuronal precursor cells, the H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes but is not essential for H3.3 localization at telomeres or at many transcription-factor binding sites; Atrx and Daxx associate with H3.3 in a Hira-independent manner and Atrx is required for Hira-independent H3.3 localization at telomeres.

    Distinct factors control histone variant H3.3 localization at specific genomic regions. · Goldberg AD, Banaszynski LA, Noh KM, et al. · Cell 2010
    PMID 20211137DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Mouse ES and neural precursor cells, not haematopoietic and not leukaemic. The zinc-finger-nuclease tag is a genome edit on one allele and the profiles are of the tagged protein. 'Required at active and repressed genes' is a genome-wide average and does not license a claim about any particular locus.

    Evidence that argues against this (1)
    • The same division of labour does not hold in blood: in fetal liver erythropoiesis HIRA is dispensable and ASF1B, not HIRA, determines H3.3 enrichment at erythroid promoters and enhancers. A chaperone assignment established in ES cells is a hypothesis in a haematopoietic cell, not a fact. Liu J et al. 2026
  2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    HIRA, UBN1, CABIN1 and ASF1a assemble into a quaternary HUCA complex reconstituted from recombinant proteins, with HIRA acting as the scaffold that brings UBN1, ASF1a and CABIN1 together; HIRA and CABIN1 regulate overlapping sets of genes that are enriched in H3.3.

    Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex. · Rai TS, Puri A, McBryan T, et al. · Molecular and Cellular Biology 2011
    PMID 21807893DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Reconstitution from recombinant proteins establishes sufficiency for assembly, not stoichiometry in a cell. The senescence and gene-overlap experiments are in human fibroblasts. No haematopoietic or leukaemic system.

    Evidence that argues against this (1)
    • HIRA's scaffold role is more constrained than a simple assembly: functional activity of the complex requires trimerization of the HIRA subunit itself, so a HIRA fragment sufficient to pull the partners down need not be sufficient for deposition. Composition mapped by co-purification overstates how interchangeable the parts are. Ray-Gallet D et al. 2018
  3. E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    HIRA expression is higher in chronic myeloid leukaemia patient samples than in healthy individuals; in a HIRA-knockdown K562 model, loss of HIRA increases chromatin compaction and shifts chromatin toward the nuclear periphery, raises H3K9me3 and HP1-alpha through SETDB1, restricts proliferation, and reduces expression of the BCR::ABL1 fusion protein.

    HIRA-SETDB1-H3K9me3 axis regulates chromatin architecture in leukemia cells. · Shirude MB, Devarajan A, Sahu SA, et al. · Journal of Biological Chemistry 2026
    PMID 42055326DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. **One cell line (K562), one knockdown, one fusion - and the fusion is BCR::ABL1, not KMT2A.** K562 is an erythroleukaemic CML line with a near-triploid genome and is a poor model of any lymphoid leukaemia. The patient-sample expression claim is reported as previous work of the same group and is not re-evidenced in this abstract. Graded moderate because the mechanism is an inference from a single knockdown in a single line and the disease is a comparator, not the index disease.

    Evidence that argues against this (1)
    • A chaperone whose loss compacts chromatin and reduces proliferation in one line has not been shown to be required in leukaemia generally. In DepMap, HIRA is broadly required (pan-essentiality -0.81 across 1,208 lines) with essentially no KMT2A-rearranged selectivity, and in the lymphoid half of the index arm the difference reverses sign. Oncofusion knowledge graph (internal analysis) 2026
  4. E4established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    Purified deposition machineries show that the H3.1 and H3.3 complexes contain distinct histone chaperones, CAF-1 and HIRA respectively, which are necessary to mediate DNA-synthesis-dependent and DNA-synthesis-independent nucleosome assembly; each complex carries one molecule each of H3.1 or H3.3 and H4, indicating H3-H4 dimers as the assembly intermediate.

    PMID 14718166DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Epitope-tagged histones expressed in HeLa cells; the complexes are what co-purifies with an over-expressed tagged histone, which biases toward stable pre-deposition intermediates. The dimer conclusion has since been refined - H3-H4 reach the nucleus as monomers in at least one route - so 'the' intermediate is not a settled single species.

    Evidence that argues against this (1)
    • Histones H3.1 and H4 can be imported into the nucleus as monomers rather than as the dimer this paper's stoichiometry implies, so the pre-deposition pathway has at least one step the 2004 purification did not resolve. Apta-Smith MJ et al. 2018
  5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    Hira is required for self-renewal of adult mouse haematopoietic stem cells and restrains erythroid differentiation: Hira deletion rapidly depletes HSCs while differentiated haematopoietic cells remain largely unaffected, with increased expression of bivalent and erythroid genes that is exacerbated on cell division, and a subset of polycomb-repressed chromatin depends on HIRA to stay inaccessible and H3.3-occupied.

    The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells. · Murdaugh RL, Hoegenauer KA, Kitano A, et al. · Stem Cell Reports 2021
    PMID 34242617DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Mouse conditional knockout, adult bone marrow, normal haematopoiesis - not leukaemia and not human. Graded strong rather than established because a directly contradicting result exists (see counter-evidence) and neither has been adjudicated.

    Evidence that argues against this (1)
    • A Nature Cell Biology paper the following year reaches the opposite conclusion in the same compartment: H3.3, but NOT its chaperone Hira, prevents premature HSC exhaustion and differentiation into granulocyte-macrophage progenitors. Two mouse conditional systems, one year apart, disagree on whether adult HSCs need HIRA. Guo P et al. 2022
  6. E6established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    As of 2026-09-20, PubMed returns 0 records for 'HIRA AND (MLL OR KMT2A)', 0 for 'HIRA AND (MLL OR KMT2A) AND leukemia', and 0 for the alias-expanded '(HIRA OR TUPLE1 OR DGCR1) AND (MLL OR KMT2A OR "mixed lineage leukemia")'. 'HIRA AND leukemia' returns 37.

    What this evidence cannot show

    Query translations were captured and none contained a [UID] term, this project's signature of a parser rewrite producing a false zero; HIRA translated as "HIRA"[All Fields], which is precise. **A bounded absence is bounded by its queries.** A paper studying HIRA in a KMT2A-rearranged model under a partner symbol (MLLT3, AFF1) rather than MLL/KMT2A, or naming HIRA only in a supplement, would not be caught - and this project has documented that AFF1 appears nowhere in the body text of a 2024 map that nonetheless recovers it.

    Evidence that argues against this (1)
    • The absence is of the symbol pair, not of the biology. A 2026 paper places HIRA mechanistically inside a leukaemia (CML) and a 2021 paper places it inside adult HSC self-renewal, so the relevant reagents, models and phenotypes already exist; nobody has pointed them at a KMT2A fusion. Shirude MB et al. 2026
  7. E7moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In DepMap CRISPR (Chronos) gene effect, HIRA's mean effect in 11 KMT2A-rearranged leukaemia lines is -0.830 against -0.749 in 43 other leukaemia lines, a difference of -0.082, at a pan-essentiality of -0.814 across 1,208 lines; split by lineage the difference is -0.147 in the 7 myeloid index lines and +0.032 in the 4 lymphoid index lines.

    What this evidence cannot show

    Run 2026-09-20. **Moderate, and the moderate grade is about what the number can be used for, not about arithmetic.** The lymphoid half is 4 cell lines. No permutation null was computed, and this project's sibling triage produced a five-gene shortlist that a 50,000-label permutation null subsequently killed. DepMap contains **no infant KMT2A::AFF1 line**. A pan-essentiality of -0.81 also means HIRA is substantially depleted everywhere, so the dynamic range in which selectivity could appear is compressed.

    Evidence that argues against this (1)
    • A CRISPR knockout screen measures loss of the whole protein over two weeks in a proliferating cell line. It cannot detect a chaperone whose contribution is to the RATE at which a mark is lost rather than to viability, which is precisely the function this beat cares about. Absence of a dependency is not absence of a role in turnover. Chory EJ et al. 2019
  8. E8strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    H3.3, but not its chaperone Hira, prevents premature haematopoietic stem cell exhaustion and differentiation into granulocyte-macrophage progenitors; H3.3-null HSPCs gain H3K27me3 at promoters of stemness and lineage genes and lose H3K9me3 at endogenous retroviral repeats.

    PMID 34961794DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Mouse, adult HSC, normal haematopoiesis. Deleting H3.3 means deleting two genes (H3f3a and H3f3b) and the abstract does not resolve which alleles were removed or whether residual H3.3 remained. The 'but not Hira' clause is the load-bearing one for this entry and is stated in the abstract without the comparison being described there.

    Evidence that argues against this (1)
    • The directly preceding paper in the same compartment reports rapid HSC depletion on Hira deletion. Both cannot be a complete account; the difference could be allele, timing, or the fact that ASF1B can deposit H3.3 without HIRA in blood. Murdaugh RL et al. 2021
  9. E9strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In mouse fetal liver haematopoiesis, HIRA is dispensable; ASF1B predominantly regulates H3.3-encoding genes and erythroid genes with ASF1A serving a compensatory function, ASF1B occupies more than 70% of H3.3 nucleosomes, and ASF1B determines H3.3 enrichment at erythroid gene promoters and enhancers.

    PMID 42100853DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Mouse fetal liver, erythroid lineage, normal development - not leukaemia. 'HIRA was dispensable' is reported as a finding of this study without the assay being named in the abstract, so the strength of that negative is unverified here; an absence of testing is not a negative result. The >70% occupancy figure is a genome-wide overlap statistic whose denominator is not stated in the abstract.

    Evidence that argues against this (1)
    • In mouse ES and neural precursor cells HIRA is required for H3.3 at active and repressed genes, so a blanket 'HIRA is dispensable for H3.3' reading would contradict the founding genome-wide study. The reconciliation is most likely cell-type-specific redundancy, which is itself the claim that matters here. Goldberg AD et al. 2010
  10. E10strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In Sp100 knockout human keratinocytes the histone chaperone HIRA and its complex members ubinuclein-1 and ASF1A fail to localise to PML nuclear bodies even after interferon stimulation; the Sp100A isoform is the primary driver of HIRA localisation and its SUMO-interacting motif is required.

    Sp100A isoform promotes localization of the histone chaperone HIRA to PML nuclear bodies. · Della Fera AN, Arman W, Powers ME, et al. · Journal of Biological Chemistry 2025
    PMID 41093075DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Normal human keratinocytes, CRISPR knockout, and the isoform mapping uses exogenous expression of Sp100 isoforms. The structural part is AlphaFold 3, Chai-1 and Boltz-2 prediction plus molecular dynamics, which is hypothesis generation and not measurement. No haematopoietic cell and no leukaemia. The authors themselves state the functional consequence is undetermined - HIRA recruitment is not required for immediate interferon signalling.

    Evidence that argues against this (1)
    • A localisation that is dispensable for the pathway it was studied in has no established function, and this graph's own condensate standard warns that punctate localisation in a heterologous or over-expression system is weak evidence about the endogenous protein. The PML-body claim should be treated as a place to look, not a mechanism. Arrieta A et al. 2022
  11. E11established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    HIRA is UniProt P54198 (HIRA_HUMAN), protein HIRA / TUP1-like enhancer of split protein 1, 1,017 amino acids, with alias symbols DGCR1, HIR and TUPLE1.

    UniProtKB P54198 (HIRA_HUMAN), Protein HIRA, 1017 aa · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
    What this evidence cannot show

    Fetched 2026-09-20 with `gene_primary` requested and read back, per rule 62: the query returned exactly one reviewed human record and its primary gene name is HIRA. No residue coordinates are stored because this entry makes no structural argument.

    Evidence that argues against this (1)
    • HIRA's alias DGCR1 names it as a 22q11 DiGeorge critical region gene, and most older literature under that symbol concerns the deletion syndrome rather than histone chaperoning. A symbol-driven literature count for 'HIRA' therefore mixes two fields and any alias-expanded search must be title-checked. US National Library of Medicine 2026
  12. E_q65_loc1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    In human keratinocytes the histone chaperone HIRA localises to PML nuclear bodies, and this is an Sp100-dependent event: Sp100 knockout abolishes HIRA, UBN1 and ASF1A localisation to PML-NBs even after interferon stimulation, the Sp100A isoform is the primary driver, and mutating Sp100A's SUMO-interacting motif impairs it.

    Sp100A isoform promotes localization of the histone chaperone HIRA to PML nuclear bodies. · Della Fera AN, et al. · J Biol Chem 2025;301:110814 2025
    PMID 41093075DOI
    What this evidence cannot show

    Normal human keratinocytes, not a haematopoietic cell and not a KMT2A-rearranged one (brief rule 73). The localisation is of HIRA to a body defined by another protein, so it is a colocalisation statement rather than an intrinsic address; the structural part of the paper is AlphaFold3/Chai-1/Boltz-2 prediction plus molecular dynamics and is not experimental. Read from the fetched abstract, not the full text.

    Evidence that argues against this (1)
    • HIRA's relationship with PML bodies is not a resting address but a transit: following type I interferon stimulus H3.3 dynamics change and HIRA's PML-NB accumulation is stimulus-dependent, so a single fixed-cell image showing HIRA in PML bodies describes a state and not a constitutive localisation. Kleijwegt C et al. 2023
  13. E_q65_loc2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In senescing human diploid fibroblasts HIRA, acting with ASF1a, drives formation of senescence-associated heterochromatin foci, and the pathway to SAHF formation has pRB-dependent, p53-dependent and independent steps - a second subnuclear compartment HIRA is documented in.

    PMID 17242198DOI
    What this evidence cannot show

    Fibroblast senescence, a system with no relationship to infant B-lineage KMT2A::AFF1. SAHF are an emergent chromatin structure rather than a pre-existing body, so 'HIRA is in SAHF' is a statement about where HIRA acts during their assembly. Abstract only.

    Evidence that argues against this (1)
    • PML itself organises heterochromatin domains and regulates H3.3 deposition there through ATRX/DAXX rather than through HIRA, so at heterochromatin the two H3.3 chaperone routes are alternatives; attributing a heterochromatic H3.3 pool to HIRA without excluding DAXX/ATRX is not safe. Delbarre E et al. 2017
  14. E_q65_loc3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

    In K562 chronic myeloid leukaemia cells - NOT a KMT2A-rearranged system - HIRA knockdown increases chromatin compaction and shifts chromatin spatial distribution toward the nuclear periphery, measured by FRAP and by FLIM-FRET microscopy, through a SETDB1/H3K9me3/HP1alpha axis.

    HIRA-SETDB1-H3K9me3 axis regulates chromatin architecture in leukemia cells. · Shirude MB, et al. · J Biol Chem 2026;302:113081 2026
    PMID 42055326DOI
    What this evidence cannot show

    This is the closest thing to a leukaemia localisation result for HIRA and it is still not one: the spatial measurement is of CHROMATIN after HIRA loss, not of HIRA. K562 carries BCR::ABL1 and no KMT2A rearrangement, and the lineage is myeloid-erythroid against this graph's infant B-lineage index disease. Read from the fetched abstract.

    Evidence that argues against this (1)
    • HDAC7 inhibition produces the apparently opposite movement on the same axis - it dissociates H3.3 from HIRA, pushes H3.3 onto DAXX and causes H3K9me3 heterochromatin SPREADING - so H3.3/HIRA and H3K9me3 are coupled in more than one direction and the K562 result cannot be read as 'HIRA opposes heterochromatin' in general. Hassan O et al. 2025
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