{"gene":"KAT6A","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2001,"finding":"MOZ (KAT6A) has intrinsic histone acetyltransferase (HAT) activity, demonstrated by direct in vitro biochemical assay. MOZ also possesses a transcriptional repression domain at its N-terminal part and a transcriptional activation domain at its C-terminal part.","method":"In vitro HAT assay, transcriptional activation assay in yeast","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay establishing HAT activity, replicated by multiple subsequent studies","pmids":["11313971"],"is_preprint":false},{"year":2001,"finding":"MOZ is part of the AML1/RUNX1 transcription factor complex and strongly stimulates AML1-mediated transcription through a potent transactivation domain (independent of its HAT activity). MOZ and CBP can each acetylate AML1 in vitro. The MOZ-CBP fusion protein inhibits AML1-mediated transcription and blocks M1 cell differentiation.","method":"Co-immunoprecipitation, reporter transcription assay, in vitro acetylation assay, cell differentiation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus in vitro acetylation plus functional reporter, replicated in subsequent studies","pmids":["11742995"],"is_preprint":false},{"year":2003,"finding":"MOZ-TIF2 fusion requires the MOZ C2HC nucleosome recognition motif for transformation of hematopoietic progenitors, whereas MOZ HAT activity is dispensable. However, recruitment of CBP through the TIF2 CBP interaction domain (CID) is essential for transformation.","method":"Murine bone marrow transplant AML model, domain-deletion mutant analysis, in vitro transformation assay","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic domain mutagenesis combined with in vivo leukemia model","pmids":["12676584"],"is_preprint":false},{"year":2008,"finding":"MOZ (KAT6A) and MORF form tetrameric complexes with ING5, EAF6, and BRPF1/2/3. BRPF1 bridges the association of MOZ/MORF with ING5 and EAF6; its N-terminal region interacts with the acetyltransferase domain of MOZ/MORF, while its EPc homology domain binds ING5 and EAF6. Complex formation with BRPF1 and ING5 drastically stimulates MOZ acetyltransferase activity toward nucleosomal H3 and free histones H3 and H4. An 18-residue C-terminal 'activation lid' on the catalytic domain is required for BRPF1 interaction.","method":"Protein reconstitution, deletion mapping, in vitro HAT assay on nucleosomal and free histones, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with HAT assay and systematic mutagenesis in a single rigorous study","pmids":["18794358"],"is_preprint":false},{"year":2006,"finding":"MOZ is required for maintenance of hematopoietic stem cells; MOZ-null mice show severe reduction of HSCs, lineage-committed progenitors, and B-lineage cells, with defective hematopoietic reconstitution. MOZ interacts with PU.1 and activates PU.1-dependent transcription, providing a physical and functional link between MOZ and myeloid differentiation. Expression of c-Mpl, HoxA9, and c-Kit is down-regulated in MOZ-deficient fetal liver.","method":"MOZ knockout mouse, bone marrow transplantation, co-immunoprecipitation, microarray, flow cytometry","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype plus Co-IP demonstrating PU.1 interaction, replicated across labs","pmids":["16702405"],"is_preprint":false},{"year":2004,"finding":"In zebrafish, moz (KAT6A ortholog) is required for maintenance of hox1-4 expression domains in pharyngeal arches and for specifying segmental identity in arches 2–4; loss of moz causes homeotic transformation of the second arch into a duplicate jaw. Rescue by the HDAC inhibitor trichostatin A indicates that HAT activity is essential for Hox gene maintenance.","method":"Forward genetic screen, positional cloning, in situ hybridization, morpholino knockdown, pharmacological rescue with TSA, epistasis with bapx1","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with pharmacological rescue establishing HAT-dependent mechanism, replicated in multiple zebrafish/mouse studies","pmids":["15128673"],"is_preprint":false},{"year":2012,"finding":"The tandem PHD finger (PHD12) of MOZ reads a combinatorial histone mark: unmodified H3R2 combined with acetylated H3K14 (H3K14ac). Crystal structure at 1.47 Å reveals the structural basis for this dual recognition. PHD12 facilitates MOZ localization to the HOXA9 gene promoter, promotes H3 acetylation around the promoter, and up-regulates HOXA9 mRNA.","method":"Crystal structure (1.47 Å), NMR, chromatin immunoprecipitation (ChIP), RT-PCR, peptide binding assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus ChIP functional validation in a single rigorous study","pmids":["22713874"],"is_preprint":false},{"year":2012,"finding":"The tandem PHD1/2 fingers of MORF (and conserved in MOZ) bind the N-terminal tail of histone H3; acetylation of H3K9 or H3K14 enhances binding 2–3-fold, while H3K4me3 inhibits binding. Both PHD fingers are required for localization to chromatin and for H3K14ac binding in vivo. The interaction with H3K14ac may promote enzymatic activity in trans.","method":"NMR, fluorescence spectroscopy, mutagenesis, HAT assay, fluorescence microscopy, immunoprecipitation","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell-based methods in one study","pmids":["23063713"],"is_preprint":false},{"year":2013,"finding":"MOZ (KAT6A) directly acetylates p53 at K120 and K382. MOZ colocalizes with p53 in PML nuclear bodies following cellular stress. The MOZ–PML–p53 ternary complex enhances MOZ-mediated p53 acetylation and p53-dependent p21 expression, inducing premature senescence. Akt-mediated phosphorylation of MOZ at T369 negatively regulates PML–MOZ complex formation, while PML-mediated suppression of Akt increases PML–MOZ interaction.","method":"In vitro acetyltransferase assay, co-immunoprecipitation, colocalization imaging, site-directed mutagenesis, reporter assays, senescence assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro acetyltransferase assay plus Co-IP and mutagenesis in a single study","pmids":["23431171"],"is_preprint":false},{"year":2008,"finding":"MOZ forms a complex with p53 to induce p21 expression and cell-cycle arrest in G1 in response to DNA damage. The p53–MOZ complex increases upon DNA damage. MOZ-deficient MEFs fail to arrest in G1 after DNA damage and show impaired p21 induction. The leukemia-associated MOZ-CBP fusion protein inhibits p53-mediated transcription.","method":"Co-immunoprecipitation, MOZ knockout MEFs, cell-cycle analysis, DNA damage assays, reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP with KO cells and defined functional phenotype, two orthogonal methods","pmids":["19001415"],"is_preprint":false},{"year":2015,"finding":"MOZ inhibits cellular senescence through the INK4A-ARF pathway: MOZ-deficient primary MEFs show premature senescence that is rescued on the Ink4a-Arf null background. This senescence is not accompanied by DNA damage. MOZ occupies the Cdc6, Ezh2, and Melk loci and maintains H3K9 and H3K27 acetylation at their transcriptional start sites; loss of MOZ reduces expression of these INK4A-ARF pathway suppressors.","method":"MOZ knockout MEFs, senescence assays (SA-β-gal), genetic rescue with Ink4a-Arf deletion, chromatin immunoprecipitation, gene expression profiling","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic rescue epistasis plus ChIP demonstrating direct chromatin occupancy, replicated across multiple labs","pmids":["25772242"],"is_preprint":false},{"year":2014,"finding":"MOZ HAT activity is required to suppress p16(INK4a) expression and protect hematopoietic and neural stem/progenitor cells from premature replicative senescence. Genetic deletion of p16(INK4a) rescues the proliferative defect in Moz HAT-deficient hematopoietic and neural progenitors.","method":"MOZ HAT-domain knock-in mouse, genetic rescue with p16INK4a deletion, progenitor proliferation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double mutant rescue in two distinct cell lineages","pmids":["24307508"],"is_preprint":false},{"year":2010,"finding":"MOZ fusion proteins (MOZ-TIF2 and MOZ-CBP) interact with PU.1 to stimulate expression of CSF1R (M-CSF receptor). PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells; CSF1R-high cells contain leukemia-initiating activity. Ablation of CSF1R-high cells cures MOZ-TIF2 AML in mice.","method":"Co-immunoprecipitation, PU.1-deficient mouse model, transgenic suicide gene under CSF1R promoter, CSF1R inhibitor treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus multiple genetic mouse models with defined leukemia phenotype","pmids":["20418886"],"is_preprint":false},{"year":2018,"finding":"KAT6A acetylates H3K23, which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling. Overexpression of acetyltransferase-deficient KAT6A mutants or TRIM24 mutants lacking H3K23ac-binding sites failed to promote PIK3CA expression, AKT phosphorylation, or cell proliferation.","method":"ChIP, siRNA knockdown, rescue with active AKT/PIK3CA overexpression, catalytic mutant analysis, in vivo orthotopic xenograft","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct chromatin mechanism plus catalytic mutant validation and in vivo rescue","pmids":["29021135"],"is_preprint":false},{"year":2018,"finding":"KAT6A biochemical inhibitors (WM-8014 and WM-1119) are reversible competitors of acetyl-CoA and inhibit MYST-catalysed histone acetylation. These inhibitors induce cell cycle exit and INK4A/ARF-dependent cellular senescence without causing DNA damage, phenocopying loss of KAT6A function.","method":"Biochemical inhibition assay, structural studies (X-ray crystallography), cellular senescence assays, gene expression profiling, zebrafish hepatocellular carcinoma model, in vivo lymphoma model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination plus biochemical and in vivo validation across multiple cancer models","pmids":["30069049"],"is_preprint":false},{"year":2002,"finding":"MOZ physically and functionally interacts with the Runt-domain transcription factor Runx2 (and Runx1/AML1) through the SM domain of MOZ/MORF. The SM domain potentiates Runx2-dependent transcriptional activation; endogenous MORF is required for Runx2-mediated transcription. Runx2 negatively regulates the transcriptional activation potential of the SM domain.","method":"In vitro pulldown, co-immunoprecipitation, reporter transcription assay, siRNA loss-of-function","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding plus functional reporter, single lab","pmids":["11965546"],"is_preprint":false},{"year":2012,"finding":"MOZ is required for expression of Tbx1 at the Tbx1 locus; the MOZ complex occupies the Tbx1 locus and promotes H3K9 acetylation there. Homozygous and haploinsufficient Moz mutant mice phenocopy DiGeorge syndrome; a Tbx1 transgene rescues the heart phenotype in Moz mutants, establishing a direct epistatic relationship.","method":"MOZ knockout and heterozygous mouse models, ChIP demonstrating MOZ occupancy at Tbx1 locus, Tbx1 transgene rescue, retinoic acid co-treatment","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus genetic epistasis (transgene rescue) in vivo","pmids":["22921202"],"is_preprint":false},{"year":2022,"finding":"KAT6A catalyzes H3K9ac at gene promoters, and this mark is specifically bound by the acetyl-lysine reader ENL. KAT6A and ENL form a 'writer-reader' epigenetic transcriptional control module that drives transcriptional elongation of leukemogenic gene-expression programs in AML. KAT6A was identified as a regulator of myeloid differentiation by differentiation-focused CRISPR screen.","method":"CRISPR screen, ChIP-seq, co-immunoprecipitation, in vitro and in vivo AML models, KAT6A inhibitor treatment","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus ChIP-seq plus Co-IP plus in vivo model, multiple orthogonal methods","pmids":["34853079"],"is_preprint":false},{"year":2021,"finding":"KAT6A acetylates SMAD3 at K20 and K117; this acetylation promotes SMAD3 association with TRIM24 and disrupts SMAD3 interaction with TRIM33. The resulting KAT6A-acetylated H3K23 recruits the TRIM24-SMAD3 complex to chromatin, increasing SMAD3 activation and cytokine expression, driving MDSC recruitment and breast cancer metastasis.","method":"Mass spectrometry, co-immunoprecipitation, in vitro acetylation assay, ChIP, xenograft mouse model, anti-PD-L1 combination therapy","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — MS identification of acetylation sites, Co-IP, ChIP and in vivo functional validation","pmids":["34392614"],"is_preprint":false},{"year":2021,"finding":"KAT6A binds to and acetylates COP1 at K294. COP1 acetylation impairs its E3 ubiquitin ligase activity toward β-catenin, leading to β-catenin accumulation and enhanced Wnt/β-catenin signaling in ovarian cancer.","method":"Mass spectrometry, co-immunoprecipitation, in vivo ubiquitination assay, in vitro acetylation assay, xenograft mouse model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro acetylation plus ubiquitination assay plus Co-IP, multiple orthogonal methods","pmids":["33995658"],"is_preprint":false},{"year":2023,"finding":"A winged helix (WH1) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs and mediates genome-wide association of KAT6A with unmethylated CpG islands (CGIs). Mutation of essential WH1 DNA-binding residues abrogates enrichment at CGIs. Overexpression of the WH1 mutant has a dominant negative effect on H3K9 histone acetylation comparable to HAT domain mutation.","method":"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, dominant-negative overexpression","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination (WH domain) plus ChIP-seq functional validation and mutagenesis","pmids":["36537216"],"is_preprint":false},{"year":2023,"finding":"MOZ and MORF contain two structured winged helix (WH) domains; WH1 specifically recognizes unmethylated CpG sequences in cooperative DNA binding. WH1 binds CpG-containing linker DNA and WH2 binds the dyad of the nucleosome (cryo-EM structure). WH1 recruits oncogenic fusions to HOXA genes, stimulating H3K23 acetylation and transcription.","method":"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus NMR plus mutagenesis plus ChIP-seq, multiple orthogonal methods in one study","pmids":["36754959"],"is_preprint":false},{"year":2013,"finding":"MOZ-TIF2 forms a stable complex with BRPF1; both MOZ-TIF2 and BRPF1 interact with HOX gene loci in MOZ-TIF2-induced AML cells. Depletion of BRPF1 decreases MOZ localization at HOX genes and abolishes MOZ-TIF2 transformation ability. A HAT-dead MOZ-TIF2 mutant cannot deregulate HOX genes or initiate leukemia, indicating that MOZ HAT activity is required for BRPF1/HOX pathway activation in AML.","method":"Co-immunoprecipitation, ChIP, BRPF1 depletion, HAT mutant, in vitro and in vivo transformation assay","journal":"International journal of hematology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP combined with HAT mutant loss-of-function and in vivo leukemia rescue","pmids":["24258712"],"is_preprint":false},{"year":2015,"finding":"MOZ and BMI1 play opposing roles during Hox gene activation: MOZ promotes and BMI1 represses Hox genes during the transition from repressed to active chromatin states. Homeotic transformations and Hox gene expression shifts in single Moz and Bmi1 mutant mice are rescued to wild-type identity in Moz;Bmi1 double-knockout animals, establishing genetic antagonism.","method":"ES cell genetic KO, double-mutant mouse epistasis, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-mutant epistasis in vivo plus ES cell genetic models, cross-validated","pmids":["25922517"],"is_preprint":false},{"year":2019,"finding":"MOZ histone acetyltransferase activity is recruited to the HCMV major immediate-early promoter by Src family kinase (HCK) activity in dendritic cells, promoting histone acetylation after ERK-mediated histone phosphorylation. Pharmacological and genetic inhibition of MOZ prevents HCMV reactivation, establishing that MOZ-dependent chromatin modification is mechanistically required for viral gene expression.","method":"Differential phosphoproteomics, pharmacological inhibition of HCK and MOZ, genetic knockdown, ChIP, viral reactivation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and pharmacological/genetic inhibition in a functional reactivation assay, single lab","pmids":["31273084"],"is_preprint":false},{"year":2016,"finding":"KAT6A (MOZ) maintains permissive Cd8 gene transcription by maintaining H3K9 acetylation at the Cd8 locus. KAT6A-deficient CD8+ T cells downregulate surface CD8 co-receptor and Cd8α transcripts during clonal expansion, reducing TCR signaling intensity and altering memory T cell subset composition.","method":"Conditional KO mice (stage-specific deletion), flow cytometry, ChIP for H3K9ac at Cd8 locus, infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP demonstrating direct chromatin mechanism at Cd8 locus, two orthogonal methods","pmids":["27653692"],"is_preprint":false},{"year":2014,"finding":"Stage-specific deletion of MOZ in germinal center B cells causes impaired generation of dark zone centroblasts, reduced cell-cycle progression and BCL-6 expression, and increased differentiation to IgM and low-affinity IgG1+ memory B cells, establishing MOZ as a regulator of germinal center fate decisions.","method":"Stage-specific conditional KO mice, flow cytometry, immunization model, BrdU proliferation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and stage-specific analysis","pmids":["24979783"],"is_preprint":false},{"year":2020,"finding":"MOZ targets a broad range of unmethylated CpG-rich promoters through association with RNA Pol II and MLL. MOZ-TIF2 and MLL-AFX leukemic fusion proteins constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells.","method":"ChIP-seq, pharmacological inhibition (MLL and DOT1L inhibitors), cell differentiation assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus pharmacological inhibitors with differentiation readout, single lab","pmids":["32997997"],"is_preprint":false},{"year":2005,"finding":"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent activators (nuclear receptors and p53) via its CBP-binding domain (AD1); MOZ-TIF2 interacts directly with CBP in vivo (co-immunoprecipitation and FRET). MOZ-TIF2 displays aberrant nuclear distribution and causes depletion of cellular CBP from PML bodies.","method":"Reporter transcription assay, co-immunoprecipitation, FRET, nuclear localization imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET plus Co-IP plus functional reporter, two orthogonal methods confirming direct interaction","pmids":["15657427"],"is_preprint":false},{"year":2003,"finding":"MOZ co-activates RUNX1-dependent transcription of the MIP-1α promoter; MOZ and RUNX1 synergistically activate this promoter. The activation is largely dependent on the proximal RUNX site; endogenous RUNX1 is constitutively bound to the endogenous MIP-1α promoter as shown by ChIP.","method":"Reporter transcription assay, in vitro DNA binding, ChIP, co-expression and mutant analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter synergy assay, single lab","pmids":["12771199"],"is_preprint":false},{"year":2024,"finding":"KAT6A deficiency impairs synaptic structure and plasticity specifically in hippocampal CA3 (not CA1), causing memory deficits in mice. RSPO2, encoding the Wnt activator R-spondin 2, is a direct transcriptional target of KAT6A in CA3. Restoring RSPO2 expression in CA3 neurons rescues Wnt signaling deficits and learning behavior in Kat6a mutant mice.","method":"Conditional KO mice, behavioral assays, electrophysiology, AAV-mediated rescue, ChIP","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic rescue plus ChIP establishing direct transcriptional target, multiple orthogonal methods","pmids":["38758792"],"is_preprint":false},{"year":2024,"finding":"KAT6A undergoes liquid-liquid phase separation (LLPS) facilitated by APEX1, forming a stable KAT6A-PARP1-APEX1 complex that reduces the amount of PARP1 trapped at DNA break sites, conferring PARP inhibitor resistance in ovarian cancer. This resistance is dependent on KAT6A LLPS rather than its catalytic activity.","method":"Co-immunoprecipitation, LLPS assay, PARP1 trapping assay, in vitro and in vivo rescue experiments","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and LLPS assay plus in vivo model, single lab","pmids":["38973255"],"is_preprint":false},{"year":2022,"finding":"MOZ and Menin-MLL chromatin regulatory complexes are cooperative dependencies in gastrointestinal stromal tumor (GIST), identified by genome-scale CRISPR screen. These complexes are enriched at GIST-relevant genes; inhibition disrupts interactions with transcriptional/chromatin regulators including DOT1L. MOZ inhibition causes significant tumor burden reduction in vivo.","method":"Genome-scale CRISPR screen, ChIP-seq, co-immunoprecipitation, MOZ inhibitor treatment, in vivo xenograft","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus ChIP-seq plus Co-IP plus in vivo model","pmids":["35499757"],"is_preprint":false},{"year":2024,"finding":"MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors by maintaining high expression levels. H3K23 propionylation (H3K23pr) enrichment positively correlates with transcription levels in MOZ-TIF2 cells, and KAT6 enzymatic activity is required for this modification and for indefinite proliferation; pharmacological inhibition or targeted protein degradation of MOZ-TIF2 abolishes proliferation.","method":"Pharmacological inhibition, targeted protein degradation (dTAG), ChIP-seq, transcriptome profiling, mouse leukemia model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — KAT6 enzymatic inhibition plus degradation plus ChIP-seq, multiple orthogonal methods","pmids":["38889153"],"is_preprint":false},{"year":2022,"finding":"Endogenous MOZ is required for AML development induced by MLL-AF9, MLL-AF10, and MOZ-TIF2 fusions; Moz-deficient HSPCs bearing MLL fusions fail to form colonies or induce AML. MOZ maintains active histone modifications (H3K4me3, H3K27ac) at the Meis1 locus in AML cells; Meis1 deletion impairs and Meis1 overexpression rescues MOZ-TIF2-mediated AML development in Moz-deficient cells.","method":"Moz conditional KO, methylcellulose colony assay, in vivo AML transplant model, ChIP, Meis1 rescue experiment","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via KO plus Meis1 rescue plus ChIP, multiple orthogonal methods","pmids":["35947126"],"is_preprint":false},{"year":2025,"finding":"KAT6A/MOZ and KAT7/HBO1 MYST HAT complex proteins associate with NUP98 fusion oncoproteins (FOs) on chromatin and within phase-separated condensates. KAT6A/7 inhibition decreases global H3K23ac, displaces NUP98::HOXA9 from the Meis1 locus, induces myeloid differentiation, and decreases leukemic burden in NUP98-rearranged xenograft mouse models.","method":"Co-immunoprecipitation, ChIP-seq, pharmacological KAT6A/7 inhibition, genetic inactivation, xenograft mouse models, differentiation assays","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus ChIP-seq plus genetic and pharmacological inhibition plus in vivo model, multiple orthogonal methods","pmids":["40536430"],"is_preprint":false},{"year":2011,"finding":"The first PHD finger (PHD1) of the MOZ complex scaffold subunit BRPF2 specifically recognizes the unmodified N-terminal tail of histone H3 (particularly unmodified R2 and K4); solution NMR structure reveals an antiparallel β-sheet pairing mechanism. Post-translational modifications H3R2me2as, H3T3ph, H3K4me/ac, and H3T6ph antagonize this interaction. PHD1-mediated histone H3 binding is required for BRPF2 localization to the HOXA9 locus in vivo.","method":"NMR structure determination, ITC, mutagenesis, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure plus ITC binding quantification plus ChIP functional validation","pmids":["21880731"],"is_preprint":false},{"year":2015,"finding":"MOZ (KAT6A) is required for expression of Tbx5 in the mesoderm; Mesp1-cre-mediated mesodermal deletion of Moz results in high-penetrance ventricular septal defects (VSDs) and overriding aorta, with decreased Tbx1 and Tbx5 expression, placing MOZ upstream of both T-box factors in cardiac development.","method":"Tissue-specific conditional KO (Mesp1-cre), echocardiography/anatomical analysis, qRT-PCR","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with defined cardiac phenotype and downstream gene expression analysis","pmids":["25912687"],"is_preprint":false},{"year":2017,"finding":"MYST3/KAT6A (MOZ) binds to the proximal promoter region of the estrogen receptor α (ERα) gene and, via its HAT domain, activates ERα transcription; inactivating HAT domain mutations abolish ERα regulation. KAT6A depletion profoundly reduces ERα expression while ectopic KAT6A increases it.","method":"ChIP demonstrating KAT6A promoter binding, HAT domain mutant analysis, siRNA knockdown, overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus HAT mutant analysis, single lab","pmids":["27893709"],"is_preprint":false},{"year":2022,"finding":"KAT6A acetylates H3K23, enhancing TRIM24 association with H3K23ac at the SOX2 promoter; TRIM24 then activates SOX2 transcription to drive hepatocellular carcinoma. KAT6A acetyltransferase-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites do not affect SOX2 expression or HCC biological function.","method":"ChIP, co-immunoprecipitation, HAT mutant analysis, SOX2 rescue experiment, in vivo xenograft","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus HAT mutant plus Co-IP, single lab","pmids":["35332266"],"is_preprint":false},{"year":2007,"finding":"MOZ directly associates with the p65 subunit of NF-κB in a protein complex and interacts directly with p65 in vitro; MOZ activates transcription from NF-κB-dependent promoters. This activation requires the C-terminal domain of MOZ (absent from MOZ-CBP), while MOZ-CBP's stronger transcriptional activity derives from the CBP portion.","method":"Co-immunoprecipitation, GST pulldown, reporter transcription assay, domain deletion analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — GST pulldown plus Co-IP plus reporter assay, single lab","pmids":["17920756"],"is_preprint":false},{"year":2016,"finding":"MOZ (KAT6A) is required for normal CD8 T cell fate: loss of MOZ reduces Cd8α transcripts and H3K9 acetylation at the Cd8 locus during clonal expansion, decreasing surface CD8 co-receptor levels and TCR signaling intensity, and accelerating contraction of the effector-like memory compartment while the long-lived memory compartment remains unaffected.","method":"Conditional KO mice, ChIP for H3K9ac at Cd8 locus, flow cytometry, viral infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP demonstrating direct H3K9ac mechanism at Cd8 locus","pmids":["27653692"],"is_preprint":false}],"current_model":"KAT6A (MOZ/MYST3) is a MYST-family lysine acetyltransferase that operates within a tetrameric complex (with BRPF1/2/3, ING5, and EAF6) to acetylate histone H3 primarily at K9, K14, K18, and K23; its catalytic domain is stimulated by BRPF1 binding via an 'activation lid', and the complex is recruited to unmethylated CpG islands genome-wide through cooperative DNA binding by two N-terminal winged helix (WH) domains (WH1 recognizes CpG motifs; WH2 contacts the nucleosome dyad), and to acetylated chromatin through tandem PHD fingers that read H3K14ac/unmodified-H3R2; at target loci KAT6A-deposited H3K9ac and H3K23ac are read by ENL and TRIM24 respectively to drive transcriptional elongation of developmental and oncogenic gene programs including HOXA genes, RSPO2, PIK3CA, ERα, SOX2, and YAP; KAT6A also acetylates non-histone substrates including p53 (K120/K382, enhanced in the MOZ-PML ternary complex), AML1/RUNX1, and SMAD3 (K20/K117), and interacts with transcription factors PU.1, NF-κB p65, and Runx2 to co-activate their target genes; loss of KAT6A causes premature senescence through de-repression of the INK4A-ARF pathway, failure to maintain hematopoietic stem cells, and cognitive deficits through impaired hippocampal CA3 RSPO2-Wnt signaling, while leukemia-associated fusion proteins (MOZ-CBP, MOZ-TIF2, MOZ-p300) aberrantly recruit CBP/p300 and constitutively activate CpG-rich promoters of self-renewal genes."},"narrative":{"mechanistic_narrative":"KAT6A (MOZ/MYST3) is a MYST-family lysine acetyltransferase that deposits histone H3 acetylation to license transcription of developmental and oncogenic gene programs and to safeguard stem/progenitor self-renewal against senescence [PMID:11313971, PMID:25772242]. Its intrinsic HAT activity [PMID:11313971] is drastically stimulated within a tetrameric complex assembled by BRPF1/2/3, which bridges KAT6A to ING5 and EAF6 and engages an 18-residue C-terminal 'activation lid' on the catalytic domain [PMID:18794358]. The complex is targeted to chromatin combinatorially: an N-terminal winged-helix domain (WH1) reads unmethylated CpG motifs to direct genome-wide enrichment at CpG islands while WH2 contacts the nucleosome dyad [PMID:36537216, PMID:36754959], and tandem PHD fingers read unmodified H3R2 together with H3K14ac to localize KAT6A at target promoters such as HOXA9 [PMID:22713874, PMID:23063713]. KAT6A-deposited H3K9ac and H3K23ac function as writer-reader modules: H3K9ac is bound by ENL to drive transcriptional elongation of leukemogenic programs [PMID:34853079], and H3K23ac recruits TRIM24 to activate PIK3CA, SOX2, and SMAD3-dependent transcription [PMID:29021135, PMID:35332266, PMID:34392614]. Through HAT-dependent maintenance of H3K9/H3K23 acetylation, KAT6A sustains Hox gene expression and segmental identity [PMID:15128673, PMID:25922517], drives the developmental T-box program (Tbx1/Tbx5) required for cardiac development [PMID:22921202, PMID:25912687], maintains hematopoietic stem cells via PU.1 [PMID:16702405], and protects progenitors from premature senescence by suppressing the INK4A-ARF pathway [PMID:25772242, PMID:24307508, PMID:30069049]. Beyond histones, KAT6A acetylates non-histone substrates including p53 (K120/K382, enhanced in PML bodies to drive p21-dependent senescence) [PMID:23431171, PMID:19001415], SMAD3 [PMID:34392614], and COP1 (to stabilize beta-catenin and enhance Wnt signaling) [PMID:33995658], and co-activates transcription factors AML1/RUNX1, Runx2, and NF-kappaB p65 [PMID:11742995, PMID:11965546, PMID:17920756]. KAT6A loss causes hippocampal CA3-specific memory deficits through impaired RSPO2-Wnt signaling [PMID:38758792]. Leukemia-associated fusions (MOZ-TIF2, MOZ-CBP) aberrantly recruit CBP/p300 to constitutively activate CpG-rich self-renewal promoters, an activity requiring nucleosome recognition and CBP recruitment more than intrinsic HAT activity in some contexts [PMID:12676584, PMID:15657427], and endogenous KAT6A is a required dependency for MLL- and NUP98-fusion-driven AML [PMID:35947126, PMID:40536430], making its catalytic and condensate-forming activities therapeutic targets [PMID:30069049, PMID:34853079, PMID:38889153].","teleology":[{"year":2001,"claim":"Established that KAT6A is itself an enzyme rather than a passive scaffold, defining its core molecular activity and bipartite repression/activation domain architecture.","evidence":"In vitro HAT assay and transcriptional domain mapping in yeast","pmids":["11313971"],"confidence":"High","gaps":["Did not identify physiological histone substrate residues","No structural basis for catalysis"]},{"year":2001,"claim":"Linked KAT6A function to a defined transcription factor program by showing it joins and transactivates the AML1/RUNX1 complex, and that the MOZ-CBP fusion subverts this to block differentiation.","evidence":"Co-IP, reporter assays, in vitro acetylation, M1 differentiation assay","pmids":["11742995"],"confidence":"High","gaps":["HAT-independence of transactivation left enzymatic role ambiguous","Endogenous AML1 target loci not mapped"]},{"year":2002,"claim":"Extended the transcription-factor partnership to Runx2 via the SM domain, generalizing KAT6A's role as a Runt-domain co-activator.","evidence":"Pulldown, Co-IP, reporter assays, siRNA loss-of-function","pmids":["11965546"],"confidence":"Medium","gaps":["Single lab","Chromatin occupancy at Runx2 targets not shown"]},{"year":2003,"claim":"Defined how the leukemic MOZ-TIF2 fusion transforms, showing nucleosome recognition and CBP recruitment—not intrinsic HAT activity—are the essential elements.","evidence":"Murine BMT AML model with domain-deletion mutants","pmids":["12676584"],"confidence":"High","gaps":["Target genes of the fusion not yet defined","Mechanism of CBP-driven activation unresolved"]},{"year":2004,"claim":"Demonstrated in vivo that KAT6A HAT activity is required to maintain Hox gene expression and segmental identity, connecting catalysis to a developmental output.","evidence":"Zebrafish forward genetics, in situ hybridization, TSA pharmacological rescue","pmids":["15128673"],"confidence":"High","gaps":["Direct chromatin occupancy at Hox loci not shown","Histone residues acetylated not identified in this system"]},{"year":2006,"claim":"Established the requirement of KAT6A for hematopoietic stem cell maintenance and linked it physically to the myeloid master regulator PU.1.","evidence":"MOZ knockout mouse, BMT, Co-IP, microarray","pmids":["16702405"],"confidence":"High","gaps":["Direct vs. indirect regulation of HSC genes not fully separated","Whether HAT activity drives PU.1 co-activation unclear"]},{"year":2008,"claim":"Resolved the complex architecture and the molecular basis of catalytic stimulation, showing BRPF1 bridges KAT6A to ING5/EAF6 and engages a C-terminal activation lid to boost nucleosomal acetylation.","evidence":"Protein reconstitution, deletion mapping, in vitro HAT assays, Co-IP","pmids":["18794358"],"confidence":"High","gaps":["Genome-wide recruitment mechanism not addressed","In vivo relevance of activation lid not tested"]},{"year":2008,"claim":"Connected KAT6A to the DNA-damage response via a p53 complex that drives p21 and G1 arrest, implicating it in tumor-suppressive checkpoint control.","evidence":"Co-IP, MOZ knockout MEFs, cell-cycle and reporter assays","pmids":["19001415"],"confidence":"High","gaps":["Acetylation sites on p53 not yet defined here","Direct vs. complex-mediated effect on p21 promoter unresolved"]},{"year":2012,"claim":"Provided the structural reading mechanism by which KAT6A and its complex are positioned on chromatin through tandem PHD recognition of combinatorial H3 marks, and linked this to HOXA9 activation.","evidence":"Crystal/NMR structures, ChIP, peptide binding, RT-PCR (PHD12 of MOZ/MORF; PHD1 of BRPF2)","pmids":["22713874","23063713","21880731"],"confidence":"High","gaps":["Did not explain initial genome-wide targeting independent of pre-existing acetylation","Quantitative contribution of each reader module unresolved"]},{"year":2012,"claim":"Placed KAT6A directly upstream of the T-box developmental program, showing its complex occupies the Tbx1 locus and that Tbx1 rescue corrects a DiGeorge-like cardiac phenotype.","evidence":"Moz KO/heterozygous mice, ChIP, Tbx1 transgene rescue","pmids":["22921202"],"confidence":"High","gaps":["Direct H3 residue acetylated at Tbx1 only inferred","Tbx5 regulation addressed only later"]},{"year":2013,"claim":"Identified KAT6A's non-histone substrate p53 (K120/K382) and a PML-body ternary complex driving senescence, with Akt phosphorylation of MOZ acting as a negative regulator.","evidence":"In vitro acetyltransferase assay, Co-IP, colocalization, mutagenesis, senescence assays","pmids":["23431171"],"confidence":"High","gaps":["Relative weight of histone vs. p53 acetylation in senescence unresolved","Stoichiometry of the ternary complex not defined"]},{"year":2013,"claim":"Showed the MOZ-TIF2 fusion depends on BRPF1 for HOX-locus localization and on HAT activity for leukemic transformation, reconciling earlier HAT-dispensability claims in a different fusion context.","evidence":"Co-IP, ChIP, BRPF1 depletion, HAT-dead mutant, in vivo transformation","pmids":["24258712"],"confidence":"High","gaps":["Apparent conflict with HAT-dispensability of MOZ-TIF2 not fully reconciled","Single fusion context"]},{"year":2015,"claim":"Established the central tumor-suppressive logic: KAT6A occupies and maintains acetylation at INK4A-ARF pathway suppressor loci, and its loss triggers premature senescence rescuable by Ink4a-Arf or p16 deletion across lineages.","evidence":"KO MEFs, HAT knock-in mice, genetic rescue epistasis, ChIP, expression profiling","pmids":["25772242","24307508"],"confidence":"High","gaps":["Precise reader of KAT6A marks at these loci not identified","Direct vs. network effects on individual targets unresolved"]},{"year":2015,"claim":"Demonstrated genetic antagonism between KAT6A and Polycomb (BMI1) at Hox loci, framing KAT6A as a counter-repressive activator in chromatin state transitions, and extended cardiac control to Tbx5.","evidence":"ES-cell KO, double-mutant epistasis, mesoderm-specific conditional KO, expression analysis","pmids":["25922517","25912687"],"confidence":"High","gaps":["Mechanistic basis of MOZ/BMI1 antagonism at chromatin not detailed","Whether antagonism is direct or via shared loci unresolved"]},{"year":2018,"claim":"Defined the H3K23ac–TRIM24 writer-reader axis driving PIK3CA/PI3K-AKT signaling, and validated catalysis as druggable with acetyl-CoA-competitive inhibitors that phenocopy KAT6A loss via INK4A/ARF senescence.","evidence":"ChIP, catalytic-mutant rescue, orthotopic xenograft; biochemical inhibitors WM-8014/WM-1119 with structural and in vivo validation","pmids":["29021135","30069049"],"confidence":"High","gaps":["Selectivity of inhibitors over related MYST enzymes in vivo","Whether senescence induction is durable in tumors unresolved"]},{"year":2021,"claim":"Expanded the non-histone substrate repertoire to SMAD3 (K20/K117) and COP1 (K294), connecting KAT6A acetylation to TGF-beta/TRIM24 signaling, MDSC-driven metastasis, and Wnt/beta-catenin stabilization.","evidence":"Mass spectrometry, Co-IP, in vitro acetylation, ubiquitination assays, ChIP, xenografts","pmids":["34392614","33995658"],"confidence":"High","gaps":["Single-lab findings for each substrate","Relative contribution of histone vs. these substrates in tumors unresolved"]},{"year":2022,"claim":"Identified the H3K9ac–ENL writer-reader module and established endogenous KAT6A as a required, druggable dependency across MLL-fusion and GIST chromatin programs via differentiation-focused and genome-scale CRISPR screens.","evidence":"CRISPR screens, ChIP-seq, Co-IP, in vivo AML/GIST models, KAT6A inhibitor; Meis1 rescue","pmids":["34853079","35499757","35947126"],"confidence":"High","gaps":["Whether ENL recruitment is the sole elongation driver unresolved","Distinguishing KAT6A catalytic from scaffolding dependency"]},{"year":2023,"claim":"Resolved the primary genome-targeting mechanism: structured tandem winged-helix domains in which WH1 reads unmethylated CpG and WH2 binds the nucleosome dyad, directing CpG-island enrichment and recruiting oncogenic fusions to HOXA genes.","evidence":"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, dominant-negative overexpression","pmids":["36537216","36754959"],"confidence":"High","gaps":["Interplay between WH-mediated CpG targeting and PHD reading of acetyl marks not fully integrated","How methylation status dynamically gates recruitment unresolved"]},{"year":2024,"claim":"Defined a tissue-specific neuronal mechanism—CA3-restricted control of RSPO2-Wnt signaling—explaining KAT6A-related cognitive deficits, with AAV RSPO2 rescue restoring learning.","evidence":"Conditional KO mice, behavior, electrophysiology, AAV rescue, ChIP","pmids":["38758792"],"confidence":"High","gaps":["Why CA3 is selectively sensitive unresolved","Whether the deficit reflects developmental vs. ongoing requirement unclear"]},{"year":2024,"claim":"Revealed a catalysis-independent function—LLPS-driven KAT6A-PARP1-APEX1 condensates that reduce PARP1 trapping and confer PARP-inhibitor resistance—broadening KAT6A's mechanistic repertoire beyond acetylation.","evidence":"Co-IP, LLPS assay, PARP1 trapping assay, in vitro/in vivo rescue","pmids":["38973255"],"confidence":"Medium","gaps":["Single lab","Structural determinants of KAT6A LLPS not defined","Generality beyond ovarian cancer unknown"]},{"year":2025,"claim":"Showed KAT6A/MYST HAT complexes associate with NUP98 fusion oncoproteins in chromatin condensates and that their inhibition displaces NUP98::HOXA9 from Meis1 and reduces leukemic burden, extending the dependency to NUP98-rearranged AML.","evidence":"Co-IP, ChIP-seq, pharmacological and genetic KAT6A/7 inhibition, xenografts, differentiation assays","pmids":["40536430"],"confidence":"High","gaps":["Whether condensate association is necessary vs. correlative for transformation unresolved","Selectivity between KAT6A and KAT7 contributions"]},{"year":null,"claim":"How KAT6A integrates its multiple recruitment modules (WH-domain CpG reading, PHD acetyl/methyl reading, RNA Pol II/MLL association) into a single locus-selection logic, and how its catalytic, scaffolding, and condensate-forming activities are partitioned across normal development versus oncogenic contexts, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking CpG-island targeting with combinatorial histone reading","Relative therapeutic weight of catalytic vs. non-catalytic functions undefined","No direct evidence in the corpus linking KAT6A to a named Mendelian disease via causative mutation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,8,13,18,19]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,18,19]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6,7,36]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[20,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,40]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,28]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,17,20,21]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,17,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,6,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,16,23,37,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,12,17,22,34,35]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10,11,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,25,26,41]}],"complexes":["KAT6A-BRPF1-ING5-EAF6 MYST acetyltransferase complex","MOZ-PML-p53 ternary complex"],"partners":["BRPF1","ING5","EAF6","PU.1","RUNX1","TRIM24","ENL","CBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92794","full_name":"Histone acetyltransferase KAT6A","aliases":["MOZ, YBF2/SAS3, SAS2 and TIP60 protein 3","MYST-3","Monocytic leukemia zinc finger protein","MOZ","Runt-related transcription factor-binding protein 2","Zinc finger protein 220"],"length_aa":2004,"mass_kda":225.0,"function":"Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro) (PubMed:11742995, PubMed:11965546). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity (PubMed:11965546). May act as a transcriptional coactivator for RUNX1 and RUNX2 (PubMed:12771199). Acetylates p53/TP53 at 'Lys-120' and 'Lys-382' and controls its transcriptional activity via association with PML (PubMed:23431171). May play a role in leukemogenic gene transcription (PubMed:39794553)","subcellular_location":"Nucleus; Nucleus, nucleolus; Nucleus, nucleoplasm; Nucleus, PML body","url":"https://www.uniprot.org/uniprotkb/Q92794/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT6A","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KAT6A","total_profiled":1310},"omim":[{"mim_id":"618217","title":"EGFR LONG NONCODING DOWNSTREAM RNA; ELDR","url":"https://www.omim.org/entry/618217"},{"mim_id":"617333","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND PTOSIS; IDDDFP","url":"https://www.omim.org/entry/617333"},{"mim_id":"616856","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN 3; BRPF3","url":"https://www.omim.org/entry/616856"},{"mim_id":"616268","title":"ARBOLEDA-THAM SYNDROME; ARTHS","url":"https://www.omim.org/entry/616268"},{"mim_id":"602410","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN; BRPF1","url":"https://www.omim.org/entry/602410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KAT6A"},"hgnc":{"alias_symbol":["MOZ"],"prev_symbol":["ZNF220","RUNXBP2","MYST3"]},"alphafold":{"accession":"Q92794","domains":[{"cath_id":"1.10.10.10","chopping":"2-79","consensus_level":"medium","plddt":88.2017,"start":2,"end":79},{"cath_id":"1.10.10.10","chopping":"98-174","consensus_level":"medium","plddt":81.5383,"start":98,"end":174},{"cath_id":"1.10.10.10","chopping":"673-777","consensus_level":"medium","plddt":90.39,"start":673,"end":777}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92794","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92794-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92794-F1-predicted_aligned_error_v6.png","plddt_mean":48.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KAT6A","jax_strain_url":"https://www.jax.org/strain/search?query=KAT6A"},"sequence":{"accession":"Q92794","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92794.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92794/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92794"}},"corpus_meta":[{"pmid":"15607963","id":"PMC_15607963","title":"MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors.","date":"2004","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/15607963","citation_count":532,"is_preprint":false},{"pmid":"9155031","id":"PMC_9155031","title":"mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9155031","citation_count":395,"is_preprint":false},{"pmid":"30069049","id":"PMC_30069049","title":"Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30069049","citation_count":244,"is_preprint":false},{"pmid":"9558366","id":"PMC_9558366","title":"A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9558366","citation_count":220,"is_preprint":false},{"pmid":"11742995","id":"PMC_11742995","title":"Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11742995","citation_count":201,"is_preprint":false},{"pmid":"18794358","id":"PMC_18794358","title":"Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18794358","citation_count":193,"is_preprint":false},{"pmid":"16702405","id":"PMC_16702405","title":"MOZ is essential for maintenance of hematopoietic stem cells.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/16702405","citation_count":173,"is_preprint":false},{"pmid":"12676584","id":"PMC_12676584","title":"MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP.","date":"2003","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/12676584","citation_count":171,"is_preprint":false},{"pmid":"11965546","id":"PMC_11965546","title":"MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11965546","citation_count":137,"is_preprint":false},{"pmid":"10824998","id":"PMC_10824998","title":"MOZ is fused to p300 in an acute monocytic leukemia with t(8;22).","date":"2000","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10824998","citation_count":136,"is_preprint":false},{"pmid":"23431171","id":"PMC_23431171","title":"MOZ increases p53 acetylation and premature senescence through its complex formation with PML.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23431171","citation_count":131,"is_preprint":false},{"pmid":"11243405","id":"PMC_11243405","title":"Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation.","date":"2001","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/11243405","citation_count":128,"is_preprint":false},{"pmid":"25728775","id":"PMC_25728775","title":"De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.","date":"2015","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25728775","citation_count":120,"is_preprint":false},{"pmid":"17694082","id":"PMC_17694082","title":"MOZ and MORF, two large MYSTic HATs in normal and cancer stem 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MOZ also possesses a transcriptional repression domain at its N-terminal part and a transcriptional activation domain at its C-terminal part.\",\n      \"method\": \"In vitro HAT assay, transcriptional activation assay in yeast\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay establishing HAT activity, replicated by multiple subsequent studies\",\n      \"pmids\": [\"11313971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MOZ is part of the AML1/RUNX1 transcription factor complex and strongly stimulates AML1-mediated transcription through a potent transactivation domain (independent of its HAT activity). MOZ and CBP can each acetylate AML1 in vitro. The MOZ-CBP fusion protein inhibits AML1-mediated transcription and blocks M1 cell differentiation.\",\n      \"method\": \"Co-immunoprecipitation, reporter transcription assay, in vitro acetylation assay, cell differentiation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus in vitro acetylation plus functional reporter, replicated in subsequent studies\",\n      \"pmids\": [\"11742995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MOZ-TIF2 fusion requires the MOZ C2HC nucleosome recognition motif for transformation of hematopoietic progenitors, whereas MOZ HAT activity is dispensable. However, recruitment of CBP through the TIF2 CBP interaction domain (CID) is essential for transformation.\",\n      \"method\": \"Murine bone marrow transplant AML model, domain-deletion mutant analysis, in vitro transformation assay\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic domain mutagenesis combined with in vivo leukemia model\",\n      \"pmids\": [\"12676584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MOZ (KAT6A) and MORF form tetrameric complexes with ING5, EAF6, and BRPF1/2/3. BRPF1 bridges the association of MOZ/MORF with ING5 and EAF6; its N-terminal region interacts with the acetyltransferase domain of MOZ/MORF, while its EPc homology domain binds ING5 and EAF6. Complex formation with BRPF1 and ING5 drastically stimulates MOZ acetyltransferase activity toward nucleosomal H3 and free histones H3 and H4. An 18-residue C-terminal 'activation lid' on the catalytic domain is required for BRPF1 interaction.\",\n      \"method\": \"Protein reconstitution, deletion mapping, in vitro HAT assay on nucleosomal and free histones, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with HAT assay and systematic mutagenesis in a single rigorous study\",\n      \"pmids\": [\"18794358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MOZ is required for maintenance of hematopoietic stem cells; MOZ-null mice show severe reduction of HSCs, lineage-committed progenitors, and B-lineage cells, with defective hematopoietic reconstitution. MOZ interacts with PU.1 and activates PU.1-dependent transcription, providing a physical and functional link between MOZ and myeloid differentiation. Expression of c-Mpl, HoxA9, and c-Kit is down-regulated in MOZ-deficient fetal liver.\",\n      \"method\": \"MOZ knockout mouse, bone marrow transplantation, co-immunoprecipitation, microarray, flow cytometry\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype plus Co-IP demonstrating PU.1 interaction, replicated across labs\",\n      \"pmids\": [\"16702405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In zebrafish, moz (KAT6A ortholog) is required for maintenance of hox1-4 expression domains in pharyngeal arches and for specifying segmental identity in arches 2–4; loss of moz causes homeotic transformation of the second arch into a duplicate jaw. Rescue by the HDAC inhibitor trichostatin A indicates that HAT activity is essential for Hox gene maintenance.\",\n      \"method\": \"Forward genetic screen, positional cloning, in situ hybridization, morpholino knockdown, pharmacological rescue with TSA, epistasis with bapx1\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with pharmacological rescue establishing HAT-dependent mechanism, replicated in multiple zebrafish/mouse studies\",\n      \"pmids\": [\"15128673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The tandem PHD finger (PHD12) of MOZ reads a combinatorial histone mark: unmodified H3R2 combined with acetylated H3K14 (H3K14ac). Crystal structure at 1.47 Å reveals the structural basis for this dual recognition. PHD12 facilitates MOZ localization to the HOXA9 gene promoter, promotes H3 acetylation around the promoter, and up-regulates HOXA9 mRNA.\",\n      \"method\": \"Crystal structure (1.47 Å), NMR, chromatin immunoprecipitation (ChIP), RT-PCR, peptide binding assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus ChIP functional validation in a single rigorous study\",\n      \"pmids\": [\"22713874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The tandem PHD1/2 fingers of MORF (and conserved in MOZ) bind the N-terminal tail of histone H3; acetylation of H3K9 or H3K14 enhances binding 2–3-fold, while H3K4me3 inhibits binding. Both PHD fingers are required for localization to chromatin and for H3K14ac binding in vivo. The interaction with H3K14ac may promote enzymatic activity in trans.\",\n      \"method\": \"NMR, fluorescence spectroscopy, mutagenesis, HAT assay, fluorescence microscopy, immunoprecipitation\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal biochemical and cell-based methods in one study\",\n      \"pmids\": [\"23063713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MOZ (KAT6A) directly acetylates p53 at K120 and K382. MOZ colocalizes with p53 in PML nuclear bodies following cellular stress. The MOZ–PML–p53 ternary complex enhances MOZ-mediated p53 acetylation and p53-dependent p21 expression, inducing premature senescence. Akt-mediated phosphorylation of MOZ at T369 negatively regulates PML–MOZ complex formation, while PML-mediated suppression of Akt increases PML–MOZ interaction.\",\n      \"method\": \"In vitro acetyltransferase assay, co-immunoprecipitation, colocalization imaging, site-directed mutagenesis, reporter assays, senescence assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro acetyltransferase assay plus Co-IP and mutagenesis in a single study\",\n      \"pmids\": [\"23431171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MOZ forms a complex with p53 to induce p21 expression and cell-cycle arrest in G1 in response to DNA damage. The p53–MOZ complex increases upon DNA damage. MOZ-deficient MEFs fail to arrest in G1 after DNA damage and show impaired p21 induction. The leukemia-associated MOZ-CBP fusion protein inhibits p53-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation, MOZ knockout MEFs, cell-cycle analysis, DNA damage assays, reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with KO cells and defined functional phenotype, two orthogonal methods\",\n      \"pmids\": [\"19001415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MOZ inhibits cellular senescence through the INK4A-ARF pathway: MOZ-deficient primary MEFs show premature senescence that is rescued on the Ink4a-Arf null background. This senescence is not accompanied by DNA damage. MOZ occupies the Cdc6, Ezh2, and Melk loci and maintains H3K9 and H3K27 acetylation at their transcriptional start sites; loss of MOZ reduces expression of these INK4A-ARF pathway suppressors.\",\n      \"method\": \"MOZ knockout MEFs, senescence assays (SA-β-gal), genetic rescue with Ink4a-Arf deletion, chromatin immunoprecipitation, gene expression profiling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic rescue epistasis plus ChIP demonstrating direct chromatin occupancy, replicated across multiple labs\",\n      \"pmids\": [\"25772242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MOZ HAT activity is required to suppress p16(INK4a) expression and protect hematopoietic and neural stem/progenitor cells from premature replicative senescence. Genetic deletion of p16(INK4a) rescues the proliferative defect in Moz HAT-deficient hematopoietic and neural progenitors.\",\n      \"method\": \"MOZ HAT-domain knock-in mouse, genetic rescue with p16INK4a deletion, progenitor proliferation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double mutant rescue in two distinct cell lineages\",\n      \"pmids\": [\"24307508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MOZ fusion proteins (MOZ-TIF2 and MOZ-CBP) interact with PU.1 to stimulate expression of CSF1R (M-CSF receptor). PU.1 is essential for MOZ-TIF2 to establish and maintain AML stem cells; CSF1R-high cells contain leukemia-initiating activity. Ablation of CSF1R-high cells cures MOZ-TIF2 AML in mice.\",\n      \"method\": \"Co-immunoprecipitation, PU.1-deficient mouse model, transgenic suicide gene under CSF1R promoter, CSF1R inhibitor treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus multiple genetic mouse models with defined leukemia phenotype\",\n      \"pmids\": [\"20418886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KAT6A acetylates H3K23, which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling. Overexpression of acetyltransferase-deficient KAT6A mutants or TRIM24 mutants lacking H3K23ac-binding sites failed to promote PIK3CA expression, AKT phosphorylation, or cell proliferation.\",\n      \"method\": \"ChIP, siRNA knockdown, rescue with active AKT/PIK3CA overexpression, catalytic mutant analysis, in vivo orthotopic xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct chromatin mechanism plus catalytic mutant validation and in vivo rescue\",\n      \"pmids\": [\"29021135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KAT6A biochemical inhibitors (WM-8014 and WM-1119) are reversible competitors of acetyl-CoA and inhibit MYST-catalysed histone acetylation. These inhibitors induce cell cycle exit and INK4A/ARF-dependent cellular senescence without causing DNA damage, phenocopying loss of KAT6A function.\",\n      \"method\": \"Biochemical inhibition assay, structural studies (X-ray crystallography), cellular senescence assays, gene expression profiling, zebrafish hepatocellular carcinoma model, in vivo lymphoma model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination plus biochemical and in vivo validation across multiple cancer models\",\n      \"pmids\": [\"30069049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MOZ physically and functionally interacts with the Runt-domain transcription factor Runx2 (and Runx1/AML1) through the SM domain of MOZ/MORF. The SM domain potentiates Runx2-dependent transcriptional activation; endogenous MORF is required for Runx2-mediated transcription. Runx2 negatively regulates the transcriptional activation potential of the SM domain.\",\n      \"method\": \"In vitro pulldown, co-immunoprecipitation, reporter transcription assay, siRNA loss-of-function\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and in vitro binding plus functional reporter, single lab\",\n      \"pmids\": [\"11965546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MOZ is required for expression of Tbx1 at the Tbx1 locus; the MOZ complex occupies the Tbx1 locus and promotes H3K9 acetylation there. Homozygous and haploinsufficient Moz mutant mice phenocopy DiGeorge syndrome; a Tbx1 transgene rescues the heart phenotype in Moz mutants, establishing a direct epistatic relationship.\",\n      \"method\": \"MOZ knockout and heterozygous mouse models, ChIP demonstrating MOZ occupancy at Tbx1 locus, Tbx1 transgene rescue, retinoic acid co-treatment\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus genetic epistasis (transgene rescue) in vivo\",\n      \"pmids\": [\"22921202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT6A catalyzes H3K9ac at gene promoters, and this mark is specifically bound by the acetyl-lysine reader ENL. KAT6A and ENL form a 'writer-reader' epigenetic transcriptional control module that drives transcriptional elongation of leukemogenic gene-expression programs in AML. KAT6A was identified as a regulator of myeloid differentiation by differentiation-focused CRISPR screen.\",\n      \"method\": \"CRISPR screen, ChIP-seq, co-immunoprecipitation, in vitro and in vivo AML models, KAT6A inhibitor treatment\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus ChIP-seq plus Co-IP plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"34853079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAT6A acetylates SMAD3 at K20 and K117; this acetylation promotes SMAD3 association with TRIM24 and disrupts SMAD3 interaction with TRIM33. The resulting KAT6A-acetylated H3K23 recruits the TRIM24-SMAD3 complex to chromatin, increasing SMAD3 activation and cytokine expression, driving MDSC recruitment and breast cancer metastasis.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vitro acetylation assay, ChIP, xenograft mouse model, anti-PD-L1 combination therapy\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS identification of acetylation sites, Co-IP, ChIP and in vivo functional validation\",\n      \"pmids\": [\"34392614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAT6A binds to and acetylates COP1 at K294. COP1 acetylation impairs its E3 ubiquitin ligase activity toward β-catenin, leading to β-catenin accumulation and enhanced Wnt/β-catenin signaling in ovarian cancer.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vivo ubiquitination assay, in vitro acetylation assay, xenograft mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro acetylation plus ubiquitination assay plus Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"33995658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A winged helix (WH1) domain at the very N-terminus of KAT6A specifically interacts with unmethylated CpG motifs and mediates genome-wide association of KAT6A with unmethylated CpG islands (CGIs). Mutation of essential WH1 DNA-binding residues abrogates enrichment at CGIs. Overexpression of the WH1 mutant has a dominant negative effect on H3K9 histone acetylation comparable to HAT domain mutation.\",\n      \"method\": \"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, dominant-negative overexpression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination (WH domain) plus ChIP-seq functional validation and mutagenesis\",\n      \"pmids\": [\"36537216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOZ and MORF contain two structured winged helix (WH) domains; WH1 specifically recognizes unmethylated CpG sequences in cooperative DNA binding. WH1 binds CpG-containing linker DNA and WH2 binds the dyad of the nucleosome (cryo-EM structure). WH1 recruits oncogenic fusions to HOXA genes, stimulating H3K23 acetylation and transcription.\",\n      \"method\": \"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus NMR plus mutagenesis plus ChIP-seq, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36754959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MOZ-TIF2 forms a stable complex with BRPF1; both MOZ-TIF2 and BRPF1 interact with HOX gene loci in MOZ-TIF2-induced AML cells. Depletion of BRPF1 decreases MOZ localization at HOX genes and abolishes MOZ-TIF2 transformation ability. A HAT-dead MOZ-TIF2 mutant cannot deregulate HOX genes or initiate leukemia, indicating that MOZ HAT activity is required for BRPF1/HOX pathway activation in AML.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, BRPF1 depletion, HAT mutant, in vitro and in vivo transformation assay\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP combined with HAT mutant loss-of-function and in vivo leukemia rescue\",\n      \"pmids\": [\"24258712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MOZ and BMI1 play opposing roles during Hox gene activation: MOZ promotes and BMI1 represses Hox genes during the transition from repressed to active chromatin states. Homeotic transformations and Hox gene expression shifts in single Moz and Bmi1 mutant mice are rescued to wild-type identity in Moz;Bmi1 double-knockout animals, establishing genetic antagonism.\",\n      \"method\": \"ES cell genetic KO, double-mutant mouse epistasis, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-mutant epistasis in vivo plus ES cell genetic models, cross-validated\",\n      \"pmids\": [\"25922517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MOZ histone acetyltransferase activity is recruited to the HCMV major immediate-early promoter by Src family kinase (HCK) activity in dendritic cells, promoting histone acetylation after ERK-mediated histone phosphorylation. Pharmacological and genetic inhibition of MOZ prevents HCMV reactivation, establishing that MOZ-dependent chromatin modification is mechanistically required for viral gene expression.\",\n      \"method\": \"Differential phosphoproteomics, pharmacological inhibition of HCK and MOZ, genetic knockdown, ChIP, viral reactivation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and pharmacological/genetic inhibition in a functional reactivation assay, single lab\",\n      \"pmids\": [\"31273084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KAT6A (MOZ) maintains permissive Cd8 gene transcription by maintaining H3K9 acetylation at the Cd8 locus. KAT6A-deficient CD8+ T cells downregulate surface CD8 co-receptor and Cd8α transcripts during clonal expansion, reducing TCR signaling intensity and altering memory T cell subset composition.\",\n      \"method\": \"Conditional KO mice (stage-specific deletion), flow cytometry, ChIP for H3K9ac at Cd8 locus, infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP demonstrating direct chromatin mechanism at Cd8 locus, two orthogonal methods\",\n      \"pmids\": [\"27653692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Stage-specific deletion of MOZ in germinal center B cells causes impaired generation of dark zone centroblasts, reduced cell-cycle progression and BCL-6 expression, and increased differentiation to IgM and low-affinity IgG1+ memory B cells, establishing MOZ as a regulator of germinal center fate decisions.\",\n      \"method\": \"Stage-specific conditional KO mice, flow cytometry, immunization model, BrdU proliferation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and stage-specific analysis\",\n      \"pmids\": [\"24979783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MOZ targets a broad range of unmethylated CpG-rich promoters through association with RNA Pol II and MLL. MOZ-TIF2 and MLL-AFX leukemic fusion proteins constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells.\",\n      \"method\": \"ChIP-seq, pharmacological inhibition (MLL and DOT1L inhibitors), cell differentiation assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus pharmacological inhibitors with differentiation readout, single lab\",\n      \"pmids\": [\"32997997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent activators (nuclear receptors and p53) via its CBP-binding domain (AD1); MOZ-TIF2 interacts directly with CBP in vivo (co-immunoprecipitation and FRET). MOZ-TIF2 displays aberrant nuclear distribution and causes depletion of cellular CBP from PML bodies.\",\n      \"method\": \"Reporter transcription assay, co-immunoprecipitation, FRET, nuclear localization imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET plus Co-IP plus functional reporter, two orthogonal methods confirming direct interaction\",\n      \"pmids\": [\"15657427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MOZ co-activates RUNX1-dependent transcription of the MIP-1α promoter; MOZ and RUNX1 synergistically activate this promoter. The activation is largely dependent on the proximal RUNX site; endogenous RUNX1 is constitutively bound to the endogenous MIP-1α promoter as shown by ChIP.\",\n      \"method\": \"Reporter transcription assay, in vitro DNA binding, ChIP, co-expression and mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter synergy assay, single lab\",\n      \"pmids\": [\"12771199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT6A deficiency impairs synaptic structure and plasticity specifically in hippocampal CA3 (not CA1), causing memory deficits in mice. RSPO2, encoding the Wnt activator R-spondin 2, is a direct transcriptional target of KAT6A in CA3. Restoring RSPO2 expression in CA3 neurons rescues Wnt signaling deficits and learning behavior in Kat6a mutant mice.\",\n      \"method\": \"Conditional KO mice, behavioral assays, electrophysiology, AAV-mediated rescue, ChIP\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic rescue plus ChIP establishing direct transcriptional target, multiple orthogonal methods\",\n      \"pmids\": [\"38758792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT6A undergoes liquid-liquid phase separation (LLPS) facilitated by APEX1, forming a stable KAT6A-PARP1-APEX1 complex that reduces the amount of PARP1 trapped at DNA break sites, conferring PARP inhibitor resistance in ovarian cancer. This resistance is dependent on KAT6A LLPS rather than its catalytic activity.\",\n      \"method\": \"Co-immunoprecipitation, LLPS assay, PARP1 trapping assay, in vitro and in vivo rescue experiments\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and LLPS assay plus in vivo model, single lab\",\n      \"pmids\": [\"38973255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MOZ and Menin-MLL chromatin regulatory complexes are cooperative dependencies in gastrointestinal stromal tumor (GIST), identified by genome-scale CRISPR screen. These complexes are enriched at GIST-relevant genes; inhibition disrupts interactions with transcriptional/chromatin regulators including DOT1L. MOZ inhibition causes significant tumor burden reduction in vivo.\",\n      \"method\": \"Genome-scale CRISPR screen, ChIP-seq, co-immunoprecipitation, MOZ inhibitor treatment, in vivo xenograft\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus ChIP-seq plus Co-IP plus in vivo model\",\n      \"pmids\": [\"35499757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MOZ-TIF2 directly regulates a small subset of genes encoding developmental transcription factors by maintaining high expression levels. H3K23 propionylation (H3K23pr) enrichment positively correlates with transcription levels in MOZ-TIF2 cells, and KAT6 enzymatic activity is required for this modification and for indefinite proliferation; pharmacological inhibition or targeted protein degradation of MOZ-TIF2 abolishes proliferation.\",\n      \"method\": \"Pharmacological inhibition, targeted protein degradation (dTAG), ChIP-seq, transcriptome profiling, mouse leukemia model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — KAT6 enzymatic inhibition plus degradation plus ChIP-seq, multiple orthogonal methods\",\n      \"pmids\": [\"38889153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endogenous MOZ is required for AML development induced by MLL-AF9, MLL-AF10, and MOZ-TIF2 fusions; Moz-deficient HSPCs bearing MLL fusions fail to form colonies or induce AML. MOZ maintains active histone modifications (H3K4me3, H3K27ac) at the Meis1 locus in AML cells; Meis1 deletion impairs and Meis1 overexpression rescues MOZ-TIF2-mediated AML development in Moz-deficient cells.\",\n      \"method\": \"Moz conditional KO, methylcellulose colony assay, in vivo AML transplant model, ChIP, Meis1 rescue experiment\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via KO plus Meis1 rescue plus ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"35947126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT6A/MOZ and KAT7/HBO1 MYST HAT complex proteins associate with NUP98 fusion oncoproteins (FOs) on chromatin and within phase-separated condensates. KAT6A/7 inhibition decreases global H3K23ac, displaces NUP98::HOXA9 from the Meis1 locus, induces myeloid differentiation, and decreases leukemic burden in NUP98-rearranged xenograft mouse models.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, pharmacological KAT6A/7 inhibition, genetic inactivation, xenograft mouse models, differentiation assays\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus ChIP-seq plus genetic and pharmacological inhibition plus in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"40536430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The first PHD finger (PHD1) of the MOZ complex scaffold subunit BRPF2 specifically recognizes the unmodified N-terminal tail of histone H3 (particularly unmodified R2 and K4); solution NMR structure reveals an antiparallel β-sheet pairing mechanism. Post-translational modifications H3R2me2as, H3T3ph, H3K4me/ac, and H3T6ph antagonize this interaction. PHD1-mediated histone H3 binding is required for BRPF2 localization to the HOXA9 locus in vivo.\",\n      \"method\": \"NMR structure determination, ITC, mutagenesis, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure plus ITC binding quantification plus ChIP functional validation\",\n      \"pmids\": [\"21880731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MOZ (KAT6A) is required for expression of Tbx5 in the mesoderm; Mesp1-cre-mediated mesodermal deletion of Moz results in high-penetrance ventricular septal defects (VSDs) and overriding aorta, with decreased Tbx1 and Tbx5 expression, placing MOZ upstream of both T-box factors in cardiac development.\",\n      \"method\": \"Tissue-specific conditional KO (Mesp1-cre), echocardiography/anatomical analysis, qRT-PCR\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with defined cardiac phenotype and downstream gene expression analysis\",\n      \"pmids\": [\"25912687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYST3/KAT6A (MOZ) binds to the proximal promoter region of the estrogen receptor α (ERα) gene and, via its HAT domain, activates ERα transcription; inactivating HAT domain mutations abolish ERα regulation. KAT6A depletion profoundly reduces ERα expression while ectopic KAT6A increases it.\",\n      \"method\": \"ChIP demonstrating KAT6A promoter binding, HAT domain mutant analysis, siRNA knockdown, overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus HAT mutant analysis, single lab\",\n      \"pmids\": [\"27893709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT6A acetylates H3K23, enhancing TRIM24 association with H3K23ac at the SOX2 promoter; TRIM24 then activates SOX2 transcription to drive hepatocellular carcinoma. KAT6A acetyltransferase-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites do not affect SOX2 expression or HCC biological function.\",\n      \"method\": \"ChIP, co-immunoprecipitation, HAT mutant analysis, SOX2 rescue experiment, in vivo xenograft\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus HAT mutant plus Co-IP, single lab\",\n      \"pmids\": [\"35332266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MOZ directly associates with the p65 subunit of NF-κB in a protein complex and interacts directly with p65 in vitro; MOZ activates transcription from NF-κB-dependent promoters. This activation requires the C-terminal domain of MOZ (absent from MOZ-CBP), while MOZ-CBP's stronger transcriptional activity derives from the CBP portion.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, reporter transcription assay, domain deletion analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — GST pulldown plus Co-IP plus reporter assay, single lab\",\n      \"pmids\": [\"17920756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MOZ (KAT6A) is required for normal CD8 T cell fate: loss of MOZ reduces Cd8α transcripts and H3K9 acetylation at the Cd8 locus during clonal expansion, decreasing surface CD8 co-receptor levels and TCR signaling intensity, and accelerating contraction of the effector-like memory compartment while the long-lived memory compartment remains unaffected.\",\n      \"method\": \"Conditional KO mice, ChIP for H3K9ac at Cd8 locus, flow cytometry, viral infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP demonstrating direct H3K9ac mechanism at Cd8 locus\",\n      \"pmids\": [\"27653692\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT6A (MOZ/MYST3) is a MYST-family lysine acetyltransferase that operates within a tetrameric complex (with BRPF1/2/3, ING5, and EAF6) to acetylate histone H3 primarily at K9, K14, K18, and K23; its catalytic domain is stimulated by BRPF1 binding via an 'activation lid', and the complex is recruited to unmethylated CpG islands genome-wide through cooperative DNA binding by two N-terminal winged helix (WH) domains (WH1 recognizes CpG motifs; WH2 contacts the nucleosome dyad), and to acetylated chromatin through tandem PHD fingers that read H3K14ac/unmodified-H3R2; at target loci KAT6A-deposited H3K9ac and H3K23ac are read by ENL and TRIM24 respectively to drive transcriptional elongation of developmental and oncogenic gene programs including HOXA genes, RSPO2, PIK3CA, ERα, SOX2, and YAP; KAT6A also acetylates non-histone substrates including p53 (K120/K382, enhanced in the MOZ-PML ternary complex), AML1/RUNX1, and SMAD3 (K20/K117), and interacts with transcription factors PU.1, NF-κB p65, and Runx2 to co-activate their target genes; loss of KAT6A causes premature senescence through de-repression of the INK4A-ARF pathway, failure to maintain hematopoietic stem cells, and cognitive deficits through impaired hippocampal CA3 RSPO2-Wnt signaling, while leukemia-associated fusion proteins (MOZ-CBP, MOZ-TIF2, MOZ-p300) aberrantly recruit CBP/p300 and constitutively activate CpG-rich promoters of self-renewal genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAT6A (MOZ/MYST3) is a MYST-family lysine acetyltransferase that deposits histone H3 acetylation to license transcription of developmental and oncogenic gene programs and to safeguard stem/progenitor self-renewal against senescence [#0, #10]. Its intrinsic HAT activity [#0] is drastically stimulated within a tetrameric complex assembled by BRPF1/2/3, which bridges KAT6A to ING5 and EAF6 and engages an 18-residue C-terminal 'activation lid' on the catalytic domain [#3]. The complex is targeted to chromatin combinatorially: an N-terminal winged-helix domain (WH1) reads unmethylated CpG motifs to direct genome-wide enrichment at CpG islands while WH2 contacts the nucleosome dyad [#20, #21], and tandem PHD fingers read unmodified H3R2 together with H3K14ac to localize KAT6A at target promoters such as HOXA9 [#6, #7]. KAT6A-deposited H3K9ac and H3K23ac function as writer-reader modules: H3K9ac is bound by ENL to drive transcriptional elongation of leukemogenic programs [#17], and H3K23ac recruits TRIM24 to activate PIK3CA, SOX2, and SMAD3-dependent transcription [#13, #39, #18]. Through HAT-dependent maintenance of H3K9/H3K23 acetylation, KAT6A sustains Hox gene expression and segmental identity [#5, #23], drives the developmental T-box program (Tbx1/Tbx5) required for cardiac development [#16, #37], maintains hematopoietic stem cells via PU.1 [#4], and protects progenitors from premature senescence by suppressing the INK4A-ARF pathway [#10, #11, #14]. Beyond histones, KAT6A acetylates non-histone substrates including p53 (K120/K382, enhanced in PML bodies to drive p21-dependent senescence) [#8, #9], SMAD3 [#18], and COP1 (to stabilize beta-catenin and enhance Wnt signaling) [#19], and co-activates transcription factors AML1/RUNX1, Runx2, and NF-kappaB p65 [#1, #15, #40]. KAT6A loss causes hippocampal CA3-specific memory deficits through impaired RSPO2-Wnt signaling [#30]. Leukemia-associated fusions (MOZ-TIF2, MOZ-CBP) aberrantly recruit CBP/p300 to constitutively activate CpG-rich self-renewal promoters, an activity requiring nucleosome recognition and CBP recruitment more than intrinsic HAT activity in some contexts [#2, #28], and endogenous KAT6A is a required dependency for MLL- and NUP98-fusion-driven AML [#34, #35], making its catalytic and condensate-forming activities therapeutic targets [#14, #17, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that KAT6A is itself an enzyme rather than a passive scaffold, defining its core molecular activity and bipartite repression/activation domain architecture.\",\n      \"evidence\": \"In vitro HAT assay and transcriptional domain mapping in yeast\",\n      \"pmids\": [\"11313971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological histone substrate residues\", \"No structural basis for catalysis\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked KAT6A function to a defined transcription factor program by showing it joins and transactivates the AML1/RUNX1 complex, and that the MOZ-CBP fusion subverts this to block differentiation.\",\n      \"evidence\": \"Co-IP, reporter assays, in vitro acetylation, M1 differentiation assay\",\n      \"pmids\": [\"11742995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HAT-independence of transactivation left enzymatic role ambiguous\", \"Endogenous AML1 target loci not mapped\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the transcription-factor partnership to Runx2 via the SM domain, generalizing KAT6A's role as a Runt-domain co-activator.\",\n      \"evidence\": \"Pulldown, Co-IP, reporter assays, siRNA loss-of-function\",\n      \"pmids\": [\"11965546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Chromatin occupancy at Runx2 targets not shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined how the leukemic MOZ-TIF2 fusion transforms, showing nucleosome recognition and CBP recruitment—not intrinsic HAT activity—are the essential elements.\",\n      \"evidence\": \"Murine BMT AML model with domain-deletion mutants\",\n      \"pmids\": [\"12676584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes of the fusion not yet defined\", \"Mechanism of CBP-driven activation unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in vivo that KAT6A HAT activity is required to maintain Hox gene expression and segmental identity, connecting catalysis to a developmental output.\",\n      \"evidence\": \"Zebrafish forward genetics, in situ hybridization, TSA pharmacological rescue\",\n      \"pmids\": [\"15128673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin occupancy at Hox loci not shown\", \"Histone residues acetylated not identified in this system\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the requirement of KAT6A for hematopoietic stem cell maintenance and linked it physically to the myeloid master regulator PU.1.\",\n      \"evidence\": \"MOZ knockout mouse, BMT, Co-IP, microarray\",\n      \"pmids\": [\"16702405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect regulation of HSC genes not fully separated\", \"Whether HAT activity drives PU.1 co-activation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the complex architecture and the molecular basis of catalytic stimulation, showing BRPF1 bridges KAT6A to ING5/EAF6 and engages a C-terminal activation lid to boost nucleosomal acetylation.\",\n      \"evidence\": \"Protein reconstitution, deletion mapping, in vitro HAT assays, Co-IP\",\n      \"pmids\": [\"18794358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide recruitment mechanism not addressed\", \"In vivo relevance of activation lid not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected KAT6A to the DNA-damage response via a p53 complex that drives p21 and G1 arrest, implicating it in tumor-suppressive checkpoint control.\",\n      \"evidence\": \"Co-IP, MOZ knockout MEFs, cell-cycle and reporter assays\",\n      \"pmids\": [\"19001415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation sites on p53 not yet defined here\", \"Direct vs. complex-mediated effect on p21 promoter unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the structural reading mechanism by which KAT6A and its complex are positioned on chromatin through tandem PHD recognition of combinatorial H3 marks, and linked this to HOXA9 activation.\",\n      \"evidence\": \"Crystal/NMR structures, ChIP, peptide binding, RT-PCR (PHD12 of MOZ/MORF; PHD1 of BRPF2)\",\n      \"pmids\": [\"22713874\", \"23063713\", \"21880731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain initial genome-wide targeting independent of pre-existing acetylation\", \"Quantitative contribution of each reader module unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed KAT6A directly upstream of the T-box developmental program, showing its complex occupies the Tbx1 locus and that Tbx1 rescue corrects a DiGeorge-like cardiac phenotype.\",\n      \"evidence\": \"Moz KO/heterozygous mice, ChIP, Tbx1 transgene rescue\",\n      \"pmids\": [\"22921202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct H3 residue acetylated at Tbx1 only inferred\", \"Tbx5 regulation addressed only later\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified KAT6A's non-histone substrate p53 (K120/K382) and a PML-body ternary complex driving senescence, with Akt phosphorylation of MOZ acting as a negative regulator.\",\n      \"evidence\": \"In vitro acetyltransferase assay, Co-IP, colocalization, mutagenesis, senescence assays\",\n      \"pmids\": [\"23431171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of histone vs. p53 acetylation in senescence unresolved\", \"Stoichiometry of the ternary complex not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the MOZ-TIF2 fusion depends on BRPF1 for HOX-locus localization and on HAT activity for leukemic transformation, reconciling earlier HAT-dispensability claims in a different fusion context.\",\n      \"evidence\": \"Co-IP, ChIP, BRPF1 depletion, HAT-dead mutant, in vivo transformation\",\n      \"pmids\": [\"24258712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent conflict with HAT-dispensability of MOZ-TIF2 not fully reconciled\", \"Single fusion context\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the central tumor-suppressive logic: KAT6A occupies and maintains acetylation at INK4A-ARF pathway suppressor loci, and its loss triggers premature senescence rescuable by Ink4a-Arf or p16 deletion across lineages.\",\n      \"evidence\": \"KO MEFs, HAT knock-in mice, genetic rescue epistasis, ChIP, expression profiling\",\n      \"pmids\": [\"25772242\", \"24307508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise reader of KAT6A marks at these loci not identified\", \"Direct vs. network effects on individual targets unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated genetic antagonism between KAT6A and Polycomb (BMI1) at Hox loci, framing KAT6A as a counter-repressive activator in chromatin state transitions, and extended cardiac control to Tbx5.\",\n      \"evidence\": \"ES-cell KO, double-mutant epistasis, mesoderm-specific conditional KO, expression analysis\",\n      \"pmids\": [\"25922517\", \"25912687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of MOZ/BMI1 antagonism at chromatin not detailed\", \"Whether antagonism is direct or via shared loci unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the H3K23ac–TRIM24 writer-reader axis driving PIK3CA/PI3K-AKT signaling, and validated catalysis as druggable with acetyl-CoA-competitive inhibitors that phenocopy KAT6A loss via INK4A/ARF senescence.\",\n      \"evidence\": \"ChIP, catalytic-mutant rescue, orthotopic xenograft; biochemical inhibitors WM-8014/WM-1119 with structural and in vivo validation\",\n      \"pmids\": [\"29021135\", \"30069049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of inhibitors over related MYST enzymes in vivo\", \"Whether senescence induction is durable in tumors unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the non-histone substrate repertoire to SMAD3 (K20/K117) and COP1 (K294), connecting KAT6A acetylation to TGF-beta/TRIM24 signaling, MDSC-driven metastasis, and Wnt/beta-catenin stabilization.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, in vitro acetylation, ubiquitination assays, ChIP, xenografts\",\n      \"pmids\": [\"34392614\", \"33995658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab findings for each substrate\", \"Relative contribution of histone vs. these substrates in tumors unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the H3K9ac–ENL writer-reader module and established endogenous KAT6A as a required, druggable dependency across MLL-fusion and GIST chromatin programs via differentiation-focused and genome-scale CRISPR screens.\",\n      \"evidence\": \"CRISPR screens, ChIP-seq, Co-IP, in vivo AML/GIST models, KAT6A inhibitor; Meis1 rescue\",\n      \"pmids\": [\"34853079\", \"35499757\", \"35947126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ENL recruitment is the sole elongation driver unresolved\", \"Distinguishing KAT6A catalytic from scaffolding dependency\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the primary genome-targeting mechanism: structured tandem winged-helix domains in which WH1 reads unmethylated CpG and WH2 binds the nucleosome dyad, directing CpG-island enrichment and recruiting oncogenic fusions to HOXA genes.\",\n      \"evidence\": \"Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, dominant-negative overexpression\",\n      \"pmids\": [\"36537216\", \"36754959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between WH-mediated CpG targeting and PHD reading of acetyl marks not fully integrated\", \"How methylation status dynamically gates recruitment unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a tissue-specific neuronal mechanism—CA3-restricted control of RSPO2-Wnt signaling—explaining KAT6A-related cognitive deficits, with AAV RSPO2 rescue restoring learning.\",\n      \"evidence\": \"Conditional KO mice, behavior, electrophysiology, AAV rescue, ChIP\",\n      \"pmids\": [\"38758792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why CA3 is selectively sensitive unresolved\", \"Whether the deficit reflects developmental vs. ongoing requirement unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a catalysis-independent function—LLPS-driven KAT6A-PARP1-APEX1 condensates that reduce PARP1 trapping and confer PARP-inhibitor resistance—broadening KAT6A's mechanistic repertoire beyond acetylation.\",\n      \"evidence\": \"Co-IP, LLPS assay, PARP1 trapping assay, in vitro/in vivo rescue\",\n      \"pmids\": [\"38973255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural determinants of KAT6A LLPS not defined\", \"Generality beyond ovarian cancer unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed KAT6A/MYST HAT complexes associate with NUP98 fusion oncoproteins in chromatin condensates and that their inhibition displaces NUP98::HOXA9 from Meis1 and reduces leukemic burden, extending the dependency to NUP98-rearranged AML.\",\n      \"evidence\": \"Co-IP, ChIP-seq, pharmacological and genetic KAT6A/7 inhibition, xenografts, differentiation assays\",\n      \"pmids\": [\"40536430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether condensate association is necessary vs. correlative for transformation unresolved\", \"Selectivity between KAT6A and KAT7 contributions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KAT6A integrates its multiple recruitment modules (WH-domain CpG reading, PHD acetyl/methyl reading, RNA Pol II/MLL association) into a single locus-selection logic, and how its catalytic, scaffolding, and condensate-forming activities are partitioned across normal development versus oncogenic contexts, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking CpG-island targeting with combinatorial histone reading\", \"Relative therapeutic weight of catalytic vs. non-catalytic functions undefined\", \"No direct evidence in the corpus linking KAT6A to a named Mendelian disease via causative mutation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 8, 13, 18, 19]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 18, 19]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6, 7, 36]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 40]},\n      {\"term_id\": \"GO:0003682\" , \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 28]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 17, 20, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 17, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 6, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 16, 23, 37, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 12, 17, 22, 34, 35]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10, 11, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 25, 26, 41]}\n    ],\n    \"complexes\": [\n      \"KAT6A-BRPF1-ING5-EAF6 MYST acetyltransferase complex\",\n      \"MOZ-PML-p53 ternary complex\"\n    ],\n    \"partners\": [\n      \"BRPF1\",\n      \"ING5\",\n      \"EAF6\",\n      \"PU.1\",\n      \"RUNX1\",\n      \"TRIM24\",\n      \"ENL\",\n      \"CBP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}