| 2001 |
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. |
In vitro HAT assay, transcriptional activation assay in yeast |
Oncogene |
High |
11313971
|
| 2001 |
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. |
Co-immunoprecipitation, reporter transcription assay, in vitro acetylation assay, cell differentiation assay |
The EMBO journal |
High |
11742995
|
| 2003 |
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. |
Murine bone marrow transplant AML model, domain-deletion mutant analysis, in vitro transformation assay |
Cancer cell |
High |
12676584
|
| 2008 |
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. |
Protein reconstitution, deletion mapping, in vitro HAT assay on nucleosomal and free histones, co-immunoprecipitation |
Molecular and cellular biology |
High |
18794358
|
| 2006 |
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. |
MOZ knockout mouse, bone marrow transplantation, co-immunoprecipitation, microarray, flow cytometry |
Genes & development |
High |
16702405
|
| 2004 |
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. |
Forward genetic screen, positional cloning, in situ hybridization, morpholino knockdown, pharmacological rescue with TSA, epistasis with bapx1 |
Development (Cambridge, England) |
High |
15128673
|
| 2012 |
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. |
Crystal structure (1.47 Å), NMR, chromatin immunoprecipitation (ChIP), RT-PCR, peptide binding assays |
Genes & development |
High |
22713874
|
| 2012 |
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. |
NMR, fluorescence spectroscopy, mutagenesis, HAT assay, fluorescence microscopy, immunoprecipitation |
Journal of molecular biology |
High |
23063713
|
| 2013 |
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. |
In vitro acetyltransferase assay, co-immunoprecipitation, colocalization imaging, site-directed mutagenesis, reporter assays, senescence assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
23431171
|
| 2008 |
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. |
Co-immunoprecipitation, MOZ knockout MEFs, cell-cycle analysis, DNA damage assays, reporter assay |
The Journal of biological chemistry |
High |
19001415
|
| 2015 |
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. |
MOZ knockout MEFs, senescence assays (SA-β-gal), genetic rescue with Ink4a-Arf deletion, chromatin immunoprecipitation, gene expression profiling |
Oncogene |
High |
25772242
|
| 2014 |
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. |
MOZ HAT-domain knock-in mouse, genetic rescue with p16INK4a deletion, progenitor proliferation assays |
Stem cells (Dayton, Ohio) |
High |
24307508
|
| 2010 |
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. |
Co-immunoprecipitation, PU.1-deficient mouse model, transgenic suicide gene under CSF1R promoter, CSF1R inhibitor treatment |
Nature medicine |
High |
20418886
|
| 2018 |
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. |
ChIP, siRNA knockdown, rescue with active AKT/PIK3CA overexpression, catalytic mutant analysis, in vivo orthotopic xenograft |
Cancer research |
High |
29021135
|
| 2018 |
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. |
Biochemical inhibition assay, structural studies (X-ray crystallography), cellular senescence assays, gene expression profiling, zebrafish hepatocellular carcinoma model, in vivo lymphoma model |
Nature |
High |
30069049
|
| 2002 |
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. |
In vitro pulldown, co-immunoprecipitation, reporter transcription assay, siRNA loss-of-function |
Oncogene |
Medium |
11965546
|
| 2012 |
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. |
MOZ knockout and heterozygous mouse models, ChIP demonstrating MOZ occupancy at Tbx1 locus, Tbx1 transgene rescue, retinoic acid co-treatment |
Developmental cell |
High |
22921202
|
| 2022 |
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. |
CRISPR screen, ChIP-seq, co-immunoprecipitation, in vitro and in vivo AML models, KAT6A inhibitor treatment |
Cancer discovery |
High |
34853079
|
| 2021 |
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. |
Mass spectrometry, co-immunoprecipitation, in vitro acetylation assay, ChIP, xenograft mouse model, anti-PD-L1 combination therapy |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
High |
34392614
|
| 2021 |
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. |
Mass spectrometry, co-immunoprecipitation, in vivo ubiquitination assay, in vitro acetylation assay, xenograft mouse model |
Theranostics |
High |
33995658
|
| 2023 |
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. |
Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, dominant-negative overexpression |
Nucleic acids research |
High |
36537216
|
| 2023 |
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. |
Cryo-EM, NMR, mass spectrometry, mutagenesis, ChIP-seq, transcriptional assays |
Nature communications |
High |
36754959
|
| 2013 |
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. |
Co-immunoprecipitation, ChIP, BRPF1 depletion, HAT mutant, in vitro and in vivo transformation assay |
International journal of hematology |
High |
24258712
|
| 2015 |
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. |
ES cell genetic KO, double-mutant mouse epistasis, gene expression analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25922517
|
| 2019 |
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. |
Differential phosphoproteomics, pharmacological inhibition of HCK and MOZ, genetic knockdown, ChIP, viral reactivation assay |
The Journal of biological chemistry |
Medium |
31273084
|
| 2016 |
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. |
Conditional KO mice (stage-specific deletion), flow cytometry, ChIP for H3K9ac at Cd8 locus, infection model |
Cell reports |
High |
27653692
|
| 2014 |
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. |
Stage-specific conditional KO mice, flow cytometry, immunization model, BrdU proliferation analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
24979783
|
| 2020 |
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. |
ChIP-seq, pharmacological inhibition (MLL and DOT1L inhibitors), cell differentiation assay |
Cell reports |
Medium |
32997997
|
| 2005 |
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. |
Reporter transcription assay, co-immunoprecipitation, FRET, nuclear localization imaging |
Molecular and cellular biology |
High |
15657427
|
| 2003 |
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. |
Reporter transcription assay, in vitro DNA binding, ChIP, co-expression and mutant analysis |
Nucleic acids research |
Medium |
12771199
|
| 2024 |
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. |
Conditional KO mice, behavioral assays, electrophysiology, AAV-mediated rescue, ChIP |
Science advances |
High |
38758792
|
| 2024 |
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. |
Co-immunoprecipitation, LLPS assay, PARP1 trapping assay, in vitro and in vivo rescue experiments |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
Medium |
38973255
|
| 2022 |
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. |
Genome-scale CRISPR screen, ChIP-seq, co-immunoprecipitation, MOZ inhibitor treatment, in vivo xenograft |
Cancer discovery |
High |
35499757
|
| 2024 |
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. |
Pharmacological inhibition, targeted protein degradation (dTAG), ChIP-seq, transcriptome profiling, mouse leukemia model |
Proceedings of the National Academy of Sciences of the United States of America |
High |
38889153
|
| 2022 |
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. |
Moz conditional KO, methylcellulose colony assay, in vivo AML transplant model, ChIP, Meis1 rescue experiment |
Blood advances |
High |
35947126
|
| 2025 |
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. |
Co-immunoprecipitation, ChIP-seq, pharmacological KAT6A/7 inhibition, genetic inactivation, xenograft mouse models, differentiation assays |
Cancer discovery |
High |
40536430
|
| 2011 |
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. |
NMR structure determination, ITC, mutagenesis, ChIP |
The Journal of biological chemistry |
High |
21880731
|
| 2015 |
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. |
Tissue-specific conditional KO (Mesp1-cre), echocardiography/anatomical analysis, qRT-PCR |
Developmental biology |
High |
25912687
|
| 2017 |
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. |
ChIP demonstrating KAT6A promoter binding, HAT domain mutant analysis, siRNA knockdown, overexpression |
Oncogene |
Medium |
27893709
|
| 2022 |
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. |
ChIP, co-immunoprecipitation, HAT mutant analysis, SOX2 rescue experiment, in vivo xenograft |
British journal of cancer |
Medium |
35332266
|
| 2007 |
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. |
Co-immunoprecipitation, GST pulldown, reporter transcription assay, domain deletion analysis |
Experimental hematology |
Medium |
17920756
|
| 2016 |
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. |
Conditional KO mice, ChIP for H3K9ac at Cd8 locus, flow cytometry, viral infection model |
Cell reports |
High |
27653692
|