{"gene":"KAT7","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1999,"finding":"HBO1 (KAT7) was identified as a novel protein that physically interacts with the human ORC1 subunit of the origin recognition complex. HBO1 exists as part of a multisubunit complex with histone H3 and H4 acetyltransferase activities, and a fraction associates with ORC1 in human cell extracts.","method":"Yeast two-hybrid screen, co-immunoprecipitation from human cell extracts, in vitro HAT assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and in vitro HAT assay; foundational paper replicated by many subsequent studies","pmids":["10438470"],"is_preprint":false},{"year":2001,"finding":"HBO1 directly interacts with MCM2 via its C2HC zinc finger domain. An N-terminal domain of MCM2 is necessary for binding HBO1, and the C2HC zinc finger of HBO1 is essential for MCM2 binding. A suppressor screen in yeast confirmed the interaction is direct and mediated by the zinc finger.","method":"Yeast two-hybrid, in vitro binding assays, in vivo co-immunoprecipitation, reverse two-hybrid selection, suppressor mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including genetic suppressor mutagenesis and in vitro reconstitution confirming direct interaction","pmids":["11278932"],"is_preprint":false},{"year":2000,"finding":"HBO1 interacts with the androgen receptor (AR) in a ligand-enhanced manner and acts as a transcriptional repressor of AR-mediated transcription. A transcriptional repression domain was mapped to the N-terminal region of HBO1. HBO1 is localized to the nucleus.","method":"Yeast two-hybrid, in vitro and in vivo co-immunoprecipitation, immunofluorescence, transient transfection reporter assays, GAL4-DBD mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (co-IP, reporter assay, domain mapping) in a single lab","pmids":["10930412"],"is_preprint":false},{"year":2006,"finding":"Hbo1 is a positive regulatory factor for pre-replication complex (pre-RC) assembly. Depletion of Hbo1 in human cells caused failure of Mcm2-7 to associate with chromatin even though ORC and Cdc6 loading was normal. Immunodepletion of Xenopus Hbo1 from egg extracts abolished MCM loading and DNA replication, which could be rescued by addition of recombinant Cdt1.","method":"siRNA knockdown in human cells, immunodepletion of Xenopus egg extracts, chromatin fractionation, recombinant protein rescue","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — complementary human cell and Xenopus egg extract systems with rescue experiment; pathway placement established","pmids":["16428461"],"is_preprint":false},{"year":2008,"finding":"HBO1 is a coactivator of the replication licensing factor Cdt1. HBO1 associates with replication origins during G1 phase in a Cdt1-dependent manner, directly interacts with Cdt1, and enhances Cdt1-dependent rereplication. This association is independent of the Cdt1 repressor Geminin.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), rereplication assay, cell-cycle fractionation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed, functional consequence demonstrated, cell-cycle regulation characterized with multiple methods","pmids":["18832067"],"is_preprint":false},{"year":2008,"finding":"Plk1 phosphorylates Hbo1 on Ser-57 in vitro and in vivo during mitosis. Cdk1 first phosphorylates Hbo1 on Thr-85/88, creating a docking site for Plk1 recruitment. The Plk1 phosphorylation-defective mutant (S57A) causes G1/S arrest, inhibits MCM chromatin loading, and reduces DNA replication.","method":"Yeast two-hybrid, in vitro kinase assay, phospho-specific antibodies, cell-cycle analysis, chromatin fractionation, overexpression of phospho-mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus in vivo phosphorylation and phospho-mutant functional analysis with defined phenotypic readouts","pmids":["18250300"],"is_preprint":false},{"year":2008,"finding":"Jade-1/1L is a crucial co-factor that positively regulates HBO1-mediated histone H4 acetylation. PHD fingers of Jade-1/1L are required for nucleosomal H4 acetylation but not for mutual binding. Co-expression of Jade-1/1L and HBO1 synergistically increases H4 acetylation in vivo and in vitro using reconstituted oligonucleosome substrates.","method":"Co-immunoprecipitation, in vitro HAT assay with oligonucleosome substrates, siRNA depletion, PHD finger deletion mutants, cell-based H4 acetylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution with nucleosomes plus in vivo corroboration and domain mapping","pmids":["18684714"],"is_preprint":false},{"year":2009,"finding":"HBO1 HAT complexes contain PHD finger domains in ING4/5 and JADE1/2/3 subunits that interact with the histone H3 N-terminal tail with distinct specificities toward its methylation status. Their combinatorial action regulates chromatin binding and substrate specificity of HBO1 complexes. HBO1 complexes are enriched throughout gene coding regions, supporting a role in transcription elongation.","method":"Biochemical analyses (pulldown, co-IP), genome-wide ChIP analysis, mutant analysis of PHD domains, cell growth assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical, genomic, functional) revealing substrate specificity mechanism","pmids":["19187766"],"is_preprint":false},{"year":2009,"finding":"Recombinant Hbo1 acetylates nucleosomal histone H4 in vitro, with a preference for lysines 5 and 12. Hbo1 protein is approximately equimolar with active replication origins in normal human fibroblasts.","method":"In vitro HAT assay with nucleosomal substrates, semi-quantitative western blot","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay in single study; preference for K5/K12 established biochemically","pmids":["19393168"],"is_preprint":false},{"year":2007,"finding":"p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Physiological stresses that stabilize p53 (hyperosmotic shock and DNA replication fork arrest) inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G1 specifically inhibits MCM2-7 chromatin loading.","method":"Co-immunoprecipitation, in vitro HAT assay, siRNA knockdown, chromatin fractionation under stress conditions","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro HAT activity assay plus in vivo epistasis; p53-dependent regulation established with multiple methods","pmids":["17954561"],"is_preprint":false},{"year":2010,"finding":"HBO1 HAT activity is essential for DNA replication licensing. A HAT-defective mutant of HBO1 bound at origins cannot load the MCM complex. H4 acetylation at origins is cell-cycle regulated (maximal at G1/S). Geminin inhibits HBO1 acetyltransferase activity in the context of a Cdt1-HBO1 complex and inhibits H4 acetylation and MCM loading in vivo.","method":"HAT-defective mutant analysis, ChIP, MCM loading assay, cell-cycle synchronization, Geminin overexpression and co-IP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic mutant establishes requirement for enzymatic activity; Geminin inhibition of complex activity demonstrated biochemically and in vivo","pmids":["20129055"],"is_preprint":false},{"year":2010,"finding":"Cdt1-induced large-scale chromatin decondensation required for MCM recruitment requires HBO1 HAT activity and histone H4 modifications. HDAC11 inhibits Cdt1-induced chromatin unfolding and MCM loading. This process is regulated positively by Cdt1 and HBO1 in G1 and repressed by Geminin-HDAC11 in S phase.","method":"Live-cell chromatin decondensation imaging, HAT-defective mutant, HDAC11 co-immunoprecipitation, MCM loading assay, cell-cycle analysis","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromatin decondensation imaging plus HAT mutant and epistasis analysis in single lab","pmids":["20980834"],"is_preprint":false},{"year":2010,"finding":"HBO1 is the major source of histone H3K14 acetylation in vivo during embryonic development. Loss of HBO1 caused >90% reduction in H3K14ac with no significant reduction at other histone residues, developmental arrest at the 10-somite stage, and decreased expression of developmental genes. No defects in DNA replication or cell proliferation were observed in primary fibroblasts from mutant embryos.","method":"Conditional knockout mouse model, quantitative western blot for multiple histone marks, gene expression analysis, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with systematic assessment of multiple histone marks identifies H3K14 as primary substrate; negative result for DNA replication also established","pmids":["21149574"],"is_preprint":false},{"year":2011,"finding":"The Hbo1-Brd1/BRPF2 complex is responsible for global acetylation of H3K14. BRD1 bridges HBO1 and its activator ING4. Depletion of Hbo1 similarly reduces H3K14 acetylation in erythroblasts, and the complex is required for fetal liver erythropoiesis and expression of key erythroid regulator genes including Gata1.","method":"Brd1-knockout mouse, biochemical co-immunoprecipitation, genome-wide ChIP mapping, western blot for H3K14ac, forced expression rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO combined with biochemical complex analysis and genome-wide ChIP; H3K14 substrate established in erythroid context","pmids":["21753189"],"is_preprint":false},{"year":2011,"finding":"JNK phosphorylates Cdt1 on threonine 29 in response to nongenotoxic stress, leading to rapid dissociation of HBO1 from replication origins and blocking DNA replication initiation. Simultaneously, JNK phosphorylates Jun (AP-1), increasing HBO1 recruitment to stress-response genes. This reciprocal regulation coordinates replication and transcription responses to stress.","method":"In vitro kinase assay, phospho-specific antibodies, ChIP, mutation of Thr29, DNA replication assay, cell-cycle analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus in vivo ChIP and phospho-mutant analysis; mechanistic switching between replication and transcription roles established","pmids":["21856198"],"is_preprint":false},{"year":2011,"finding":"ING4/5 PHD domain association with HBO1-JADE determines the growth inhibitory function of the complex, linked to tumor suppressor activity. HBO1/ING complexes are a major source of H3 and H4 acetylation in vivo. The p53/p21 pathway is a main transcriptional target regulated directly at the p21/CDKN1A initiation site.","method":"Molecular dissection of protein domains, co-immunoprecipitation, ChIP, PHD mutant analysis, cell growth assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping plus ChIP and functional analysis in single lab","pmids":["22144582"],"is_preprint":false},{"year":2012,"finding":"Plk1 phosphorylation of Hbo1 transcriptionally increases cFos expression and consequently elevates MDR1, conferring gemcitabine resistance in pancreatic cancer. Cells expressing Plk1-unphosphorylatable Hbo1 mutants are more sensitive to gemcitabine.","method":"Phospho-mutant overexpression, gene expression analysis, drug sensitivity assays, xenograft mouse model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-mutant analysis with in vivo xenograft validation; single lab","pmids":["23188630"],"is_preprint":false},{"year":2013,"finding":"Hbo1 is a cyclin E/CDK2 substrate; CDK2 phosphorylates Hbo1 at T88. The low-molecular weight cyclin E (LMW-E)/CDK2 complex phosphorylates Hbo1 at T88 without affecting its HAT activity. Wild-type Hbo1 coexpressed with LMW-E/CDK2 promotes cancer stem-like cell enrichment, whereas the T88A mutant reverses this phenotype.","method":"Protein microarray, in vitro kinase assay, phospho-mutant analysis, cancer stem cell (CD44hi/CD24lo) flow cytometry, mammosphere formation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus phospho-mutant functional analysis; single lab","pmids":["23955388"],"is_preprint":false},{"year":2013,"finding":"Fbxw15 directly interacts with HBO1 and mediates its ubiquitination at Lys338 and proteasomal degradation in the cytoplasm. Mek1 triggers HBO1 phosphorylation and degradation, and this process requires Fbxw15. Fbxw15-mediated HBO1 depletion reduces H3K14 acetylation and cellular proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, mass spectrometry (Lys338 site), siRNA knockdown, cell proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination site identified by MS, co-IP and functional consequences; single lab","pmids":["23319590"],"is_preprint":false},{"year":2013,"finding":"Hbo1 promotes proteasome-dependent degradation of estrogen receptor α (ERα) through lysine 48-linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its ERα ubiquitination activity. Hbo1 depletion increases ERα expression.","method":"siRNA knockdown, ubiquitination assay, western blot, K48-linked ubiquitin chain analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and depletion phenotype; single lab","pmids":["24125069"],"is_preprint":false},{"year":2015,"finding":"UV damage triggers ATM/ATR-dependent phosphorylation of HBO1 on Ser50 and Ser53, which causes preferential interaction with DDB2 and subsequent ubiquitylation by CRL4DDB2, leading to HBO1 degradation and suppression of cell proliferation. Ser50/53Ala mutants maintain H3K14ac and impair cell-cycle regulation in response to UV.","method":"Phospho-specific antibodies, co-immunoprecipitation, ubiquitination assay, CRL4DDB2 reconstitution, phospho-mutant analysis, UV survival assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation sites mapped, E3 ligase identified, phospho-mutant functional analysis; mechanistically comprehensive in single study","pmids":["26572825"],"is_preprint":false},{"year":2015,"finding":"BRPF3 specifically forms a tetrameric complex with HBO1 (not with related acetyltransferases MOZ, MORF, TIP60, or MOF) and this complex specifically acetylates histone H3K14.","method":"Affinity purification, co-immunoprecipitation, western blot for histone marks, LacZ reporter mouse","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex specificity established by co-IP; H3K14 substrate confirmed; single lab","pmids":["26677226"],"is_preprint":false},{"year":2015,"finding":"BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14. BRPF3 and HBO1 are enriched at ORC1-binding sites and replication origins near TSSs. BRPF3 is required for H3K14ac at selected origins and for efficient CDC45 recruitment (origin activation), but not for MCM2-7 loading, defining a distinct licensing-independent role in origin firing.","method":"RNAi screen for replication regulators, co-immunoprecipitation, genome-wide ChIP-seq, origin firing assay (CDC45 vs MCM loading by ChIP)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide analysis plus functional dissection distinguishing licensing vs. origin activation steps; orthogonal methods","pmids":["26620551"],"is_preprint":false},{"year":2016,"finding":"KAT7 interacts with the CENP-A assembly factor M18BP1. KAT7 knockout in HeLa cells reduces centromeric CENP-A assembly and increases mitotic chromosome misalignment and micronuclei formation. Tethering KAT7 to an ectopic alphoid DNA site removes H3K9me3 and stimulates CENP-A or H3.3 assembly, antagonizing Suv39h1-mediated heterochromatin invasion.","method":"Co-immunoprecipitation, CRISPR knockout, immunofluorescence for CENP-A and H3K9me3, tethering assay at ectopic alphoid DNA locus","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus tethering experiment with multiple functional readouts; mechanism of CENP-A assembly competence defined","pmids":["27270040"],"is_preprint":false},{"year":2016,"finding":"KAT7 interacts with the N-terminal domain (NTD) of progesterone receptor (PR) in a ligand-dependent manner via its MYST domain and induces SRC-1-dependent coactivation of PR-mediated transcription. HBO1 also interacts with SRC-1a. In HEK293 cells, HBO1 selectively enhances PRB but not PRA transcriptional activity.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transient transfection reporter assays, immunofluorescence, RT-PCR of endogenous target genes","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (yeast 2H, GST pulldown, reporter assay) in single lab; domain mapped","pmids":["16645042"],"is_preprint":false},{"year":2017,"finding":"The crystal structure of the HBO1 MYST domain in complex with the N-terminal region of BRPF2 reveals key residues for the HBO1-BRPF2 interaction. The N-terminal region of BRPF2 is sufficient to bind HBO1 and potentiate its HAT activity toward H3K14 (free H3, H4, and nucleosomal H3).","method":"Crystal structure determination, in vitro HAT assay, mutagenesis of key interface residues, cell biological validation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro enzymatic assay and mutagenesis; multiple orthogonal methods in single study","pmids":["28334966"],"is_preprint":false},{"year":2017,"finding":"Phosphorylated HBO1 at CPD (cyclobutane pyrimidine dimer) sites mediates histone acetylation to facilitate XPC recruitment at UV-damaged DNA sites. HBO1 also facilitates accumulation of SNF2H-ACF1 chromatin remodeling complex at CPD sites. HBO1 depletion inhibits CPD repair and sensitizes cells to UV.","method":"siRNA knockdown, immunofluorescence at UV-damage sites, co-immunoprecipitation with DDB2, epistasis in XP patient-derived cells, UV survival assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis analysis in XP-patient cells plus localization and functional data; mechanistic order in NER pathway established","pmids":["28719581"],"is_preprint":false},{"year":2017,"finding":"Hbo1 has intrinsic ubiquitin E3 ligase activity toward ERα. Estradiol-17β inhibits this E3 ligase activity in vitro, while hyperactive ERα mutants from metastatic breast cancers are better substrates for Hbo1-mediated ubiquitination.","method":"In vitro ubiquitination assay, Hbo1 knockdown, western blot","journal":"Proceedings of the Japan Academy. Series B, Physical and biological sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro E3 ligase assay in single study; intrinsic E3 activity established biochemically","pmids":["28769019"],"is_preprint":false},{"year":2018,"finding":"JADE1 physically links the catalytic HBO1 subunit with its histone H3-H4 substrate. JADE1 increases catalytic efficiency of HBO1 acetylation of H3-H4 substrate ~5-fold through an N-terminal 21-residue HBO1- and histone-binding domain. HBO1 also contains an N-terminal histone-binding domain (HBD) that makes additional H3-H4 contacts but does not significantly contribute to overall HAT activity.","method":"In vitro reconstitution with recombinant proteins, kinetic enzyme assays, JADE1 deletion mapping, in vivo validation by deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetic analysis plus in vivo corroboration; mechanism of JADE1-mediated substrate presentation defined","pmids":["29382722"],"is_preprint":false},{"year":2018,"finding":"KAT7 mediates H3K14 and H4 acetylation in intragenic regions of EC-enriched genes including VEGFR-2, contributing to RNA polymerase II binding and VEGFR-2 transcription. KAT7 depletion reduces VEGFR-2 expression and disrupts angiogenic potential. KAT7 inhibition in zebrafish disrupts vessel formation, which is rescued by human KAT7.","method":"siRNA knockdown, ChIP with tiling array, microarray, KAT7 inhibition in zebrafish embryos, rescue with human KAT7","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus KD phenotype and zebrafish rescue; single lab","pmids":["29414790"],"is_preprint":false},{"year":2018,"finding":"LPS elevates HBO1 protein stability by upregulating the deubiquitinase USP25, which associates with HBO1 and suppresses its ubiquitination. Stabilized HBO1 then modulates inflammatory gene transcription in THP-1 monocytes.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of USP25, western blot, LPS treatment","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay demonstrating USP25-dependent deubiquitination; single lab","pmids":["30745998"],"is_preprint":false},{"year":2019,"finding":"The histone acetyltransferase domain of HBO1 is essential for H3K14 acetylation in AML LSCs. H3K14ac facilitates RNA polymerase II processivity to maintain high expression of HOXA9/HOXA10. A competitive acetyl-CoA analogue inhibitor (WM-3835) inhibits HBO1, recapitulating genetic loss-of-function in AML.","method":"CRISPR domain screen, quantitative mass spectrometry, H3K14ac ChIP-seq, RNA pol II ChIP-seq, shRNA screen in LSC model, small-molecule inhibitor characterization (competitive kinetics with acetyl-CoA)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR domain screen, biochemical mechanism of inhibitor action, ChIP-seq, and primary patient AML cells; multiple orthogonal methods across labs","pmids":["31827282"],"is_preprint":false},{"year":2019,"finding":"LYAR recruits KAT7 to rDNA loci via BRD2 and BRD4 interactions, resulting in enhanced local acetylation of histone H4 at rDNA, thereby promoting rRNA synthesis. BRD2 is required for KAT7 recruitment; LYAR also binds a BRD4-KAT7 complex that independently promotes H4 and H3 acetylation at rDNA.","method":"Co-immunoprecipitation, ChIP-qPCR, siRNA knockdown, rRNA synthesis measurement","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP demonstrate recruitment mechanism; single lab","pmids":["31504794"],"is_preprint":false},{"year":2019,"finding":"UHRF1 interacts with methylated H3K14 and thereby suppresses H3K14 acetylation by KAT7, leading to transcriptional repression of the tumor suppressor TUSC3 in colon cancer cells.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, western blot for H3K14ac","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and co-IP supporting crosstalk between H3K14 methylation and acetylation; single lab","pmids":["31582837"],"is_preprint":false},{"year":2019,"finding":"Myst2/Kat7 interacts with the tumour suppressor protein Niam (Nuclear Interactor of ARF and Mdm2) in mouse embryonic stem cells, as identified by affinity purification-mass spectrometry. Myst2 forms both H3 and H4 histone acetylation complexes in ESCs similar to those in somatic cells.","method":"Affinity purification coupled to mass spectrometry (AP-MS) in mouse ESCs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — AP-MS identifies interaction; limited functional follow-up for the specific Niam interaction in this paper","pmids":["28811661"],"is_preprint":false},{"year":2020,"finding":"KAT7 knockout in HeLa and 293T human cells demonstrates that HBO1 is essential for all H3K14ac but is dispensable for H4 acetylation and DNA replication in human cells. Loss of HBO1 and H3K14ac secondarily causes near-complete loss of H4 acetylation after 4 weeks. HBO1 loss principally affects cell adhesion genes.","method":"CRISPR/Cas9 knockout, siRNA knockdown in multiple human cell lines, western blot for multiple histone marks, cell proliferation assay, transcriptomic analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO in multiple cell lines with comprehensive histone mark analysis; negative result for H4ac and DNA replication role firmly established","pmids":["31767635"],"is_preprint":false},{"year":2020,"finding":"KAT7 loss in AML cells driven by MLL-X fusions leads to rapid and complete loss of both H3K14ac and H4K12ac, reduced proliferation, apoptosis, and differentiation. Loss of these marks causes BRD4 and AF4 to dissociate from MLL-fusion target gene promoters (MEIS1, PBX3, SENP6), implicating acetylated histones as a platform for MLL-fusion adaptor recruitment.","method":"Genome-wide CRISPR screen, CRISPR KO, ChIP-seq for histone marks and co-factors, gene expression analysis, differentiation assays","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen followed by ChIP-seq mechanistic analysis; pathway placement established","pmids":["32764680"],"is_preprint":false},{"year":2020,"finding":"Protein kinase D1 (PKD1) directly interacts with and phosphorylates KAT7 at Thr97 and Thr331. PKD1-mediated phosphorylation enhances KAT7 stability by reducing ubiquitination-mediated degradation. Phospho-defective mutant KAT7-T97/331A attenuates H4 acetylation, MCM2/6 chromatin loading, DNA replication, and cell proliferation.","method":"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant analysis, ubiquitination assay, chromatin fractionation, BrdU incorporation","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay and phospho-mutant phenotype; single lab","pmids":["33014433"],"is_preprint":false},{"year":2021,"finding":"HBO1 is a versatile histone acyltransferase that catalyzes not only histone acetylation but also propionylation, butyrylation, and crotonylation in vivo and in vitro, and does so in a JADE or BRPF scaffold protein-dependent manner. The minimal HBO1/BRPF2 complex accommodates acetyl-CoA, propionyl-CoA, butyryl-CoA, and crotonyl-CoA. HBO1 is the key enzyme for H3K14 acylations at transcription start sites.","method":"In vitro acylation assays with different acyl-CoA substrates, in vivo acylation by mass spectrometry, genome-wide ChIP for acylation marks, CBP vs HBO1 comparison with KO cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with multiple acyl-CoA substrates plus genome-wide in vivo corroboration; comprehensive biochemical characterization","pmids":["34259319"],"is_preprint":false},{"year":2021,"finding":"Leukemic MLL fusion proteins associate with the HBO1 HAT complex through their trithorax homology domain 2 (THD2) via ING4/5 and PHF16 subunits. MLL-ELL particularly depends on this association for leukemic transformation. HBO1 complex promotes loading of the AF4/ENL/P-TEFb (AEP) complex onto target promoters over EAF1 and p53. The NUP98-HBO1 fusion exerts oncogenic properties via interaction with MLL, not its intrinsic HAT activity.","method":"Co-immunoprecipitation in multiple human cell lines, ChIP, leukemic transformation assay in murine hematopoietic progenitors, domain deletion and HAT-dead mutant analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic domain dissection, and functional leukemia transformation assays; HAT-independent mechanism for NUP98-HBO1 established","pmids":["34431785"],"is_preprint":false},{"year":2022,"finding":"HBO1 is required for H3K14ac throughout the genome in hematopoietic stem cells (HSCs). Loss of HBO1 causes abnormally high recruitment of quiescent HSCs into the cell cycle, leading to HSC pool exhaustion. HBO1 promotes expression of a transcription factor network (Mpl, Tek, Gfi1b, Egr1, Tal1, Gata2, Erg, Pbx1, Meis1, Hox9) essential for HSC quiescence and self-renewal.","method":"Conditional KO (Mx1-Cre and Rosa26-CreERT2), competitive transplantation, cell-cycle analysis, H3K14ac ChIP-seq, gene expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary Cre systems, competitive transplantation, ChIP-seq; mechanism established in vivo","pmids":["34724565"],"is_preprint":false},{"year":2022,"finding":"HBO1 catalyzes lysine benzoylation (Kbz) in mammalian cells, acting as a 'writer' of this modification. At least 77 HBO1-targeted Kbz sites were identified in the benzoylome, including at chromatin-related proteins.","method":"In vitro benzoylation assay, mass spectrometry-based benzoylome analysis in KO cells, western blot","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus KO-based proteomics; single lab","pmids":["36388951"],"is_preprint":false},{"year":2022,"finding":"SIRT1 deacetylates KAT7, activating it. SIRT1 loss leads to hyperacetylation of KAT7 and reduced H4K12ac. Overexpression of a non-acetylatable KAT7 mutant partly rescues SIRT1 loss-induced proliferation defects in T-ALL, establishing a NOTCH1-SIRT1-KAT7 regulatory axis.","method":"Global acetyl proteomics upon SIRT1 loss, KAT7 non-acetylatable mutant rescue, H4K12ac measurement, gene expression profiling","journal":"Blood cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetyl proteomics identifies KAT7 acetylation site; non-acetylatable mutant rescue supports mechanism; single lab","pmids":["36322781"],"is_preprint":false},{"year":2022,"finding":"KAT7 mediates the K525 crotonylation of CANX (calnexin). Loss of KAT7 renders MTORC1 insensitive to leucine deprivation. KAT7-mediated CANX K525 crotonylation is required for lysosomal translocation of CANX and subsequent inhibition of Ragulator activity toward RRAG GTPases during leucine deprivation.","method":"Cell-free MTORC1 activation system, co-immunoprecipitation, site-specific crotonylation mutagenesis (K525), KAT7 KO, lysosomal fractionation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — non-histone substrate (CANX K525cr) identified with KO and site-specific mutant; single lab","pmids":["35266843"],"is_preprint":false},{"year":2022,"finding":"KAT7 is required for optimal expansion of medullary thymic epithelial cells (mTECs) and for expression of AIRE-dependent peripheral tissue genes (PTGs), associated with enhanced chromatin accessibility at PTG loci. TEC-specific Kat7 deletion leads to organ-specific autoimmunity resembling Aire-deficient mice.","method":"Conditional TEC-specific KO, ATAC-seq for chromatin accessibility, gene expression analysis, histological assessment of autoimmunity","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional TEC KO with ATAC-seq mechanistic analysis and in vivo autoimmunity phenotype; pathway position established","pmids":["35061506"],"is_preprint":false},{"year":2023,"finding":"HBO1 functions as a lysine lactyltransferase: it catalyzes the addition of lysine lactylation (Kla) in vitro and intracellularly. E508 is a key site for lactyltransferase activity. HBO1 preferentially catalyzes histone H3K9la. Scaffold proteins JADE1 and BRPF2 promote enzymatic activity for histone Kla. H3K9la at TSSs is required for gene transcription.","method":"In vitro lactyltransferase assay, E508 mutagenesis, quantitative proteomics of Kla sites in KO cells, site-specific antibodies, CUT&Tag for H3K9la at TSSs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, quantitative proteomics, and genome-wide CUT&Tag; multiple orthogonal methods in single comprehensive study","pmids":["38670996"],"is_preprint":false},{"year":2023,"finding":"KAT7 is required for neural stem cell plasticity and de novo gene activation. KAT7 and H3K14ac are present at inactive genes, intergenic regions, and in heterochromatin — not only at transcribed genes. KAT7 is not required for continued transcription of already-active genes but is indispensable for activation of repressed genes. Loss of KAT7 abolishes neural stem cell differentiation pathways; re-expression restores developmental potential.","method":"Conditional KO, H3K14ac ChIP-seq, gene expression profiling, neural stem cell differentiation assays, KAT7 re-expression rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq and functional rescue; mechanistic distinction between gene maintenance vs. activation established","pmids":["36641753"],"is_preprint":false},{"year":2023,"finding":"Identification of histone lysine acetoacetylation (Kacac) as a novel post-translational modification. HBO1, traditionally an acetyltransferase, also serves as an acetoacetyltransferase, adding acetoacetyl groups to histones. 33 Kacac sites on mammalian histones were identified.","method":"HPLC co-elution, MS/MS analysis with synthetic peptides, western blot, isotopic labeling, in vitro acetoacetyltransferase assay","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biochemical validation approaches for novel modification; single lab discovery study","pmids":["37382194"],"is_preprint":false},{"year":2023,"finding":"HBO1 interacts with SMAD4 and co-binds open chromatin marked by H3K14ac and H3K4me3 in undifferentiated hESCs to maintain pluripotency. Upon BMP4-induced differentiation, HBO1/SMAD4 co-occupy mesoderm gene loci. HBO1-null hESCs fail to respond to TGF-β signaling to maintain pluripotency and cannot form mesendoderm.","method":"Co-immunoprecipitation, ChIP-seq for HBO1 and SMAD4, conditional KO hESCs, differentiation assays (gastruloids, teratomas)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP-seq, and KO hESC functional assays establish mechanistic interaction with TGF-β/SMAD pathway","pmids":["38421638"],"is_preprint":false},{"year":2023,"finding":"NLRP11 bridges KAT7 to vimentin, enabling KAT7 to directly acetylate vimentin at Lys104. NLRP11 also induces cytoplasmic localization of KAT7 to facilitate vimentin K104Ac. This acetylation promotes EMT and malignant behavior in lung adenocarcinoma.","method":"Co-immunoprecipitation, in vitro acetylation assay (KAT7 + vimentin substrate), site-specific K104Q/R mutations, subcellular fractionation, in vivo xenograft","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro acetylation of non-histone substrate validated with co-IP and site-specific mutants; single lab","pmids":["37424170"],"is_preprint":false},{"year":2023,"finding":"KAT7 acetylates H3K14 to enhance MRAS transcription, activating the MAPK/ERK pathway in colorectal cancer. Re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescues MRAS expression and ERK phosphorylation after KAT7 knockdown.","method":"shRNA knockdown, CRISPR KO, acetyltransferase-dead mutant rescue, RNA-seq, ChIP-qPCR for H3K14ac at MRAS promoter, ERK phosphorylation western blot","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetyltransferase-dead mutant rescue plus ChIP confirms mechanism; single lab","pmids":["39816686"],"is_preprint":false},{"year":2024,"finding":"The PZP (PHD1-zinc-knuckle-PHD2) domain of JADE engages the nucleosome through binding to histone H3 and DNA, directing the HBO1 complex to chromatin targets. Recognition of unmethylated H3K4 by PZP directs enzymatic activity toward histone H4 acetylation, whereas H3K4 hypermethylation alters histone substrate selectivity. These structural findings were linked to leukemogenesis via the NUP98-JADE2 fusion.","method":"Structural analysis of PZP domain, genomic binding studies (ChIP-seq), complex assembly in vivo, nucleosome-binding assays, leukemic transformation assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structural + biochemical nucleosome binding + genomic + functional leukemia assay; mechanism of complex recruitment and substrate selectivity established","pmids":["38448574"],"is_preprint":false},{"year":2024,"finding":"KAT7 crotonylation at K432 (facilitated by hMOF) competes against its acetylation (regulated by HDAC2) at the same residue upon DNA damage. This competition reduces HBO1 histone acetyltransferase activity, leading to decreased H3K14ac at procentriole formation gene promoters and inhibition of procentriole formation.","method":"Site-specific K432 crotonylation/acetylation mutants, in vitro HAT assay, co-IP with hMOF/HDAC2, ChIP-qPCR for H3K14ac, procentriole formation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assay with site-specific mutants plus ChIP and functional procentriole assay; competitive modification mechanism established","pmids":["40064919"],"is_preprint":false},{"year":2025,"finding":"KAT7 and KAT6A associate with NUP98 fusion oncoproteins on chromatin and within phase-separated condensates via the common subunit BRPF1. Genetic inactivation or pharmacologic inhibition of KAT7 decreases global H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and leads to myeloid differentiation. KAT6A/7 inhibition is efficacious in menin inhibitor-resistant NUP98-rearranged leukemia.","method":"CRISPR genetic inactivation, pharmacologic inhibition, ChIP-seq for H3K23ac and NUP98 fusion, co-IP, in vivo xenograft mouse models, synergy analysis with menin inhibitor","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq mechanistic analysis, co-IP, multiple in vivo xenograft models, and drug combination testing; comprehensive study","pmids":["40536430"],"is_preprint":false},{"year":2025,"finding":"Loss of KAT7 suppresses KAT7-mediated acetylation of the transcriptional repressor RFX1, stabilizing RFX1 (by blocking its proteasomal degradation) and thereby suppressing FGF1 transcription, leading to neuronal damage. NgBR regulates this axis by controlling KAT7 expression.","method":"RNA sequencing, co-immunoprecipitation (KAT7-RFX1 interaction), KAT7 KO, western blot for RFX1 stability, FGF1 transcription analysis, neuronal apoptosis assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and KO with defined substrate and functional consequence; single lab, non-histone substrate","pmids":["40192836"],"is_preprint":false},{"year":2024,"finding":"KAT7 acetylates LDHA at lysine 118 in head and neck squamous carcinoma (HNSCC), enhancing LDHA activity and upregulating LDHA protein expression, thereby promoting the Warburg effect and tumor proliferation/metastasis.","method":"Co-immunoprecipitation, in vitro acetylation assay, site-specific K118 mutation, lactate production assay, KAT7 KO/OE with LDHA rescue, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro acetylation assay with site-specific mutant plus functional metabolic readout; single lab, non-histone substrate","pmids":["38593918"],"is_preprint":false},{"year":2020,"finding":"MEAF6 modulates KAT7 complex assembly; in the absence of MEAF6, KAT7 increases its ability to interact with PHD-finger proteins (Brpfs/Jades). MEAF6 is essential for cell proliferation but not for HAT activity itself.","method":"Inducible Meaf6 KO in mouse ES cells, co-immunoprecipitation, histone acetylation western blot, cell proliferation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus co-IP establishing modulatory role in complex assembly; single lab","pmids":["32918898"],"is_preprint":false},{"year":2020,"finding":"BRPF3-mediated degradation pathway: the E3 ligase HUWE1 mediates ubiquitin-dependent degradation of Myst2/KAT7, and BRPF3 antagonizes HUWE1-mediated Myst2 degradation by direct protein-protein interaction, retaining Myst2 stability. This balance is required for normal differentiation and cell-cycle progression in embryonic stem cells.","method":"Co-immunoprecipitation, ubiquitination assay, BRPF3/HUWE1 overexpression/KD, Myst2 stability western blot, ESC differentiation assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ubiquitination assay establishing HUWE1 as E3 ligase and BRPF3 as antagonist; single lab","pmids":["32555450"],"is_preprint":false},{"year":2006,"finding":"HBO1 inhibits NF-κB activity by coactivator sequestration (squelching), not by binding p65/RelA or disrupting NF-κB DNA binding. The N-terminal serine-rich region of HBO1 (not its acetyltransferase domain) is required for this inhibitory activity.","method":"Reporter gene assay, EMSA, NF-κB component overexpression, N-terminal deletion mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with negative EMSA result and functional reporter assay; single lab","pmids":["16997280"],"is_preprint":false},{"year":2007,"finding":"FAD24 interacts with HBO1 and recruits it to origins of DNA replication during late mitosis (when the pre-RC is assembled). When fad24 is knocked down, recruitment of HBO1 to origins is reduced, impairing mitotic clonal expansion during adipogenesis.","method":"Co-immunoprecipitation, ChIP at replication origins, siRNA knockdown, colocalization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP demonstrating FAD24-dependent recruitment to origins; single lab","pmids":["18029353"],"is_preprint":false},{"year":2021,"finding":"HBO1 promotes angiogenic tip cell sprouting through maintaining H3K14ac and appropriate gene expression in endothelial cells. Loss of HBO1 impairs developmental sprouting angiogenesis; single-cell RNA-seq reveals increased tip cell abundance and overcrowding in the sprouting front.","method":"Endothelial-specific conditional KO, retinal wholemount imaging, single-cell RNA-seq, H3K14ac ChIP-seq","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with single-cell RNA-seq and genome-wide ChIP-seq; mechanistic basis for tip cell regulation established","pmids":["34550360"],"is_preprint":false}],"current_model":"KAT7/HBO1/MYST2 is a MYST-family lysine acetyltransferase that exists in two principal tetrameric complexes—one containing JADE1/2/3 scaffold proteins (which directs H4K5/8/12 acetylation) and one containing BRPF1/2/3 scaffold proteins (which directs H3K14 acetylation)—and it is the major cellular source of H3K14 acetylation in vivo; it functions as a coactivator of the replication licensing factor Cdt1 by acetylating histone H4 at origins to facilitate MCM2-7 loading, is regulated by cell-cycle kinases (Cdk1, Plk1, PKD1) through phosphorylation that modulates its stability and activity, is degraded after DNA damage via CRL4DDB2-mediated ubiquitination (dependent on ATM/ATR phosphorylation), and beyond histones catalyzes acylation of non-histone substrates including calnexin K525cr, LDHA K118ac, vimentin K104ac, and RFX1, while also acting as an E3 ubiquitin ligase for ERα; at the genomic level, KAT7-dependent H3K14ac is a prerequisite for de novo gene activation (but not maintenance of ongoing transcription), centromere integrity (by antagonizing Suv39h1-mediated H3K9me3), AIRE-dependent peripheral tolerance gene expression in thymic epithelial cells, HSC quiescence and self-renewal, and is co-opted by oncogenic MLL-fusion proteins and NUP98-fusion proteins to maintain leukemia stem cell transcriptional programs."},"narrative":{"mechanistic_narrative":"KAT7 (HBO1/MYST2) is a MYST-family lysine acetyltransferase that operates as the catalytic engine of multisubunit chromatin-modifying complexes and is the major cellular source of histone H3K14 acetylation in vivo [PMID:21149574, PMID:31767635]. Its substrate specificity and chromatin targeting are dictated by mutually exclusive scaffold subunits: JADE1/2/3 directs acetylation toward histone H4 (K5/K12), while BRPF1/2/3 directs activity toward H3K14, with ING4/5 and the PHD/PZP modules of these partners reading the H3 tail to govern recruitment and substrate choice [PMID:18684714, PMID:19187766, PMID:21753189, PMID:26677226, PMID:38448574]. Structural and kinetic studies show JADE1 presents the H3-H4 substrate to the MYST domain to boost catalytic efficiency, and a defined BRPF2-MYST interface potentiates H3K14 activity [PMID:28334966, PMID:29382722]. Beyond acetylation, the same enzyme is a versatile acyltransferase that installs propionyl, butyryl, crotonyl, benzoyl, acetoacetyl, and lactyl marks in a scaffold-dependent manner, with H3K14 acylation and H3K9 lactylation at transcription start sites required for gene transcription [PMID:34259319, PMID:36388951, PMID:38670996, PMID:37382194]. Functionally, KAT7-dependent H3K14ac is a prerequisite for de novo activation of repressed genes rather than maintenance of ongoing transcription, underlies neural and embryonic stem cell plasticity, hematopoietic stem cell quiescence and self-renewal, AIRE-dependent peripheral tolerance gene expression in thymic epithelium, and centromere integrity through antagonism of Suv39h1-mediated H3K9me3 to license CENP-A assembly [PMID:27270040, PMID:34724565, PMID:35061506, PMID:36641753, PMID:38421638]. In its earliest-characterized role KAT7 acts as a coactivator of the licensing factor Cdt1, acetylating histone H4 at origins to drive chromatin decondensation and MCM2-7 loading, a function gated by p53, Geminin, and cell-cycle kinases [PMID:16428461, PMID:18832067, PMID:20129055]. KAT7 stability and activity are tightly controlled by phosphorylation (Cdk1/Plk1, CDK2, PKD1, JNK, ATM/ATR), competing acyl modifications, deacetylation by SIRT1, and ubiquitin ligases (CRL4DDB2, Fbxw15, HUWE1) opposed by deubiquitinase USP25 and the stabilizing partner BRPF3 [PMID:18250300, PMID:21856198, PMID:26572825, PMID:30745998, PMID:33014433, PMID:36322781, PMID:32555450]. KAT7 also acetylates non-histone substrates including calnexin K525cr (mTORC1 signaling), LDHA K118 (the Warburg effect), vimentin K104 (EMT), and RFX1, and is co-opted by oncogenic MLL-fusion and NUP98-fusion proteins to sustain leukemia stem cell transcriptional programs, making it a therapeutic target in AML [PMID:31827282, PMID:32764680, PMID:34431785, PMID:35266843, PMID:37424170, PMID:40536430, PMID:38593918].","teleology":[{"year":1999,"claim":"Established KAT7 as a chromatin-associated acetyltransferase physically tied to the replication machinery, framing it as a candidate link between histone modification and origin function.","evidence":"Yeast two-hybrid, co-IP, and in vitro HAT assay identifying HBO1 as an ORC1-interacting protein with H3/H4 acetyltransferase activity","pmids":["10438470"],"confidence":"High","gaps":["Did not show whether HAT activity is required at origins","Complex composition and scaffold subunits unknown"]},{"year":2001,"claim":"Defined a direct, domain-specific physical bridge between KAT7 and the MCM helicase, anchoring it mechanistically to pre-replication complex components.","evidence":"Yeast two-hybrid, in vitro binding, suppressor mutagenesis mapping MCM2 binding to the HBO1 C2HC zinc finger","pmids":["11278932"],"confidence":"High","gaps":["Functional consequence of MCM2 binding for replication not yet tested","Did not implicate acetylation activity"]},{"year":2006,"claim":"Placed KAT7 functionally upstream of MCM loading, showing it is required for pre-RC assembly downstream of ORC/Cdc6.","evidence":"siRNA in human cells and immunodepletion of Xenopus egg extracts with recombinant Cdt1 rescue and chromatin fractionation","pmids":["16428461"],"confidence":"High","gaps":["Did not establish whether enzymatic activity versus scaffolding drives MCM loading","Histone substrate at origins not defined"]},{"year":2008,"claim":"Identified KAT7 as a Cdt1 coactivator and revealed cell-cycle kinase control of its replication function, integrating it into G1/S licensing regulation.","evidence":"Co-IP, ChIP, rereplication assays for Cdt1 interaction; in vitro/in vivo kinase assays and phospho-mutants for Cdk1-primed Plk1 phosphorylation at Ser57","pmids":["18832067","18250300"],"confidence":"High","gaps":["How phosphorylation alters complex composition not resolved","Direct origin acetyl substrate still inferred"]},{"year":2010,"claim":"Demonstrated that KAT7 catalytic activity, not just binding, is essential for replication licensing via H4 acetylation-driven chromatin decondensation, and is restrained by Geminin and p53.","evidence":"HAT-defective mutants, ChIP, MCM loading assays, Geminin co-IP, live-cell decondensation imaging, and p53-dependent HAT inhibition assays","pmids":["20129055","20980834","17954561"],"confidence":"High","gaps":["Quantitative contribution of H4 acetylation versus other marks at origins unclear","Crosstalk between p53 and Geminin regulation not integrated"]},{"year":2011,"claim":"Resolved the scaffold logic dividing KAT7 activity into JADE-directed H4 acetylation and BRPF-directed H3K14 acetylation, and assigned KAT7 as the principal in vivo source of H3K14ac.","evidence":"JADE1 PHD reconstitution HAT assays, Brd1/BRPF2 KO mouse with genome-wide ChIP, and a conditional Hbo1 KO mouse profiling multiple histone marks","pmids":["18684714","21753189","21149574","19187766","19393168"],"confidence":"High","gaps":["Structural basis of scaffold-imposed specificity not yet solved at this stage","Why H3K14ac loss arrests development mechanistically undefined"]},{"year":2015,"claim":"Distinguished a licensing-independent role for the HBO1-BRPF3 complex in origin firing and uncovered DNA-damage-triggered destruction of KAT7, linking it to genome surveillance.","evidence":"RNAi screen, ChIP-seq, and CDC45-versus-MCM assays for BRPF3; ATM/ATR phospho-site mapping (Ser50/53) with CRL4DDB2 reconstitution for damage-induced degradation","pmids":["26620551","26677226","26572825"],"confidence":"High","gaps":["How a single enzyme partitions between licensing and firing roles unresolved","In vivo relevance of damage-induced degradation to repair outcomes incomplete"]},{"year":2017,"claim":"Provided structural definition of the BRPF2-MYST interface and JADE1-mediated substrate presentation, and positioned KAT7 in nucleotide excision repair chromatin remodeling.","evidence":"Crystal structure of MYST-BRPF2 with HAT assays and mutagenesis; kinetic reconstitution of JADE1-stimulated catalysis; UV-damage localization and XP-cell epistasis for NER","pmids":["28334966","29382722","28719581"],"confidence":"High","gaps":["Full holocomplex structure not determined","Relative importance of NER role versus replication role in vivo unclear"]},{"year":2016,"claim":"Established KAT7's role in centromere maintenance by enabling CENP-A assembly through antagonism of Suv39h1 heterochromatin, broadening its function beyond replication and transcription.","evidence":"Co-IP with M18BP1, CRISPR KO with CENP-A/H3K9me3 immunofluorescence, and ectopic tethering at alphoid DNA","pmids":["27270040"],"confidence":"High","gaps":["Whether centromeric function requires a specific scaffold complex not defined","Direct acetyl substrate at centromeres not pinpointed"]},{"year":2020,"claim":"Decoupled KAT7's histone substrates in human cells, showing it is essential for all H3K14ac but dispensable for replication, overturning the obligatory licensing role and refocusing on transcriptional output.","evidence":"CRISPR KO in multiple human cell lines with comprehensive histone-mark westerns and transcriptomics, plus complex-assembly studies of MEAF6 and HUWE1/BRPF3-controlled stability","pmids":["31767635","32918898","32555450"],"confidence":"High","gaps":["Reconciliation with earlier Xenopus/human replication-licensing data not fully explained","Cell-type dependence of replication role unresolved"]},{"year":2022,"claim":"Defined KAT7 as a stem-cell and tolerance regulator that activates gene programs through genome-wide H3K14ac, and expanded its catalytic repertoire to non-acetyl acylations and non-histone substrates.","evidence":"Conditional KO with transplantation and ChIP-seq in HSCs; TEC-specific KO with ATAC-seq for AIRE-dependent genes; in vitro acylation and proteomics for crotonyl/benzoyl marks; CANX K525cr mTORC1 system","pmids":["34724565","35061506","38670996","36388951","35266843","36322781"],"confidence":"High","gaps":["How a single enzyme selects among diverse acyl-CoA cosubstrates in vivo unclear","Physiological abundance of rarer acylations uncertain"]},{"year":2023,"claim":"Crystallized the principle that KAT7/H3K14ac licenses de novo gene activation rather than maintenance, and connected the complex to pluripotency and signaling pathways.","evidence":"Conditional KO with ChIP-seq and rescue in neural stem cells; HBO1-SMAD4 co-IP/ChIP-seq in hESCs with differentiation assays; lactyl/acetoacetyl transferase characterization","pmids":["36641753","38421638","38670996","37382194"],"confidence":"High","gaps":["Mechanism distinguishing activatable from maintained genes not fully defined","Whether acylation marks (lactyl) drive distinct gene programs unclear"]},{"year":2025,"claim":"Consolidated KAT7 as a therapeutic target in fusion-driven leukemias, showing oncogenic MLL- and NUP98-fusions co-opt the KAT7 complex and its acetyl marks to sustain leukemia stem cell programs.","evidence":"CRISPR screens, ChIP-seq for histone marks and fusion proteins, co-IP via BRPF1, small-molecule HBO1 inhibitors, and xenograft/menin-inhibitor combination studies","pmids":["31827282","32764680","34431785","40536430"],"confidence":"High","gaps":["Therapeutic window between leukemic dependence and normal HSC requirement not defined","Relative contribution of H3K14ac, H4K12ac, and H3K23ac to fusion recruitment varies between studies"]},{"year":null,"claim":"How KAT7 integrates its many regulatory inputs (competing acylations at K432, phosphorylation, deacetylation, scaffold choice) to select among histone and non-histone substrates in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking PTM state to substrate/scaffold selection","Quantitative hierarchy of competing acyl-CoA cosubstrates in vivo unknown","Structure of full holocomplex on nucleosome not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[8,12,13,25,28,38,41,45,47,49,55]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[43,49,50,54,55]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[19,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,24,46,48]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7,28,51]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,24]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[4,23]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,49]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,13,35,38,46]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[46,48,50,45]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[3,4,10,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[31,36,39,53]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,23,52]}],"complexes":["HBO1-JADE complex","HBO1-BRPF complex","ORC/pre-replication complex (associated)"],"partners":["JADE1","BRPF2","BRPF3","ING4","MCM2","CDT1","ORC1","MEAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95251","full_name":"Histone acetyltransferase KAT7","aliases":["Histone acetyltransferase binding to ORC1","Lysine acetyltransferase 7","MOZ, YBF2/SAS3, SAS2 and TIP60 protein 2","MYST-2"],"length_aa":611,"mass_kda":70.6,"function":"Catalytic subunit of histone acetyltransferase HBO1 complexes, which specifically mediate acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby regulating various processes, such as gene transcription, protein ubiquitination, immune regulation, stem cell pluripotent and self-renewal maintenance and embryonic development (PubMed:16387653, PubMed:21753189, PubMed:24065767, PubMed:26620551, PubMed:31767635, PubMed:31827282). Some complexes also catalyze acetylation of histone H4 at 'Lys-5', 'Lys-8' and 'Lys-12' (H4K5ac, H4K8ac and H4K12ac, respectively), regulating DNA replication initiation, regulating DNA replication initiation (PubMed:10438470, PubMed:19187766, PubMed:20129055, PubMed:24065767). Specificity of the HBO1 complexes is determined by the scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE (JADE1, JADE2 and JADE3) scaffold direct KAT7/HBO1 specificity towards histone H4 (PubMed:19187766, PubMed:20129055, PubMed:24065767, PubMed:26620551). H3K14ac promotes transcriptional elongation by facilitating the processivity of RNA polymerase II (PubMed:31827282). Acts as a key regulator of hematopoiesis by forming a complex with BRD1/BRPF2, directing KAT7/HBO1 specificity towards H3K14ac and promoting erythroid differentiation (PubMed:21753189). H3K14ac is also required for T-cell development (By similarity). KAT7/HBO1-mediated acetylation facilitates two consecutive steps, licensing and activation, in DNA replication initiation: H3K14ac facilitates the activation of replication origins, and histone H4 acetylation (H4K5ac, H4K8ac and H4K12ac) facilitates chromatin loading of MCM complexes, promoting DNA replication licensing (PubMed:10438470, PubMed:11278932, PubMed:18832067, PubMed:19187766, PubMed:20129055, PubMed:21856198, PubMed:24065767, PubMed:26620551). Acts as a positive regulator of centromeric CENPA assembly: recruited to centromeres and mediates histone acetylation, thereby preventing centromere inactivation mediated by SUV39H1, possibly by increasing histone turnover/exchange (PubMed:27270040). Involved in nucleotide excision repair: phosphorylation by ATR in response to ultraviolet irradiation promotes its localization to DNA damage sites, where it mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites (PubMed:28719581). Acts as an inhibitor of NF-kappa-B independently of its histone acetyltransferase activity (PubMed:16997280) Plays a central role in the maintenance of leukemia stem cells in acute myeloid leukemia (AML) (PubMed:31827282). Acts by mediating acetylation of histone H3 at 'Lys-14' (H3K14ac), thereby facilitating the processivity of RNA polymerase II to maintain the high expression of key genes, such as HOXA9 and HOXA10 that help to sustain the functional properties of leukemia stem cells (PubMed:31827282)","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O95251/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT7","classification":"Not 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cells.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28811661","citation_count":13,"is_preprint":false},{"pmid":"33014433","id":"PMC_33014433","title":"Protein kinase D1 phosphorylation of KAT7 enhances its protein stability and promotes replication licensing and cell proliferation.","date":"2020","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33014433","citation_count":13,"is_preprint":false},{"pmid":"23707616","id":"PMC_23707616","title":"Expression and characterization of androgen receptor coregulators, SRC-2 and HBO1, during human testis ontogenesis and in androgen signaling deficient patients.","date":"2013","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23707616","citation_count":13,"is_preprint":false},{"pmid":"38593918","id":"PMC_38593918","title":"KAT7 enhances the proliferation and metastasis of head and neck squamous carcinoma by promoting the acetylation level of LDHA.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/38593918","citation_count":12,"is_preprint":false},{"pmid":"37258203","id":"PMC_37258203","title":"The lncRNA ADAMTS9-AS1/miR-185-5p/KAT7 ceRNA network inhibits cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy.","date":"2023","source":"Biomedical research (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/37258203","citation_count":12,"is_preprint":false},{"pmid":"40064919","id":"PMC_40064919","title":"Competitive antagonism of KAT7 crotonylation against acetylation affects procentriole formation and colorectal tumorigenesis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40064919","citation_count":11,"is_preprint":false},{"pmid":"39543485","id":"PMC_39543485","title":"Multifunctional acyltransferase HBO1: a key regulatory factor for cellular functions.","date":"2024","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/39543485","citation_count":11,"is_preprint":false},{"pmid":"38448574","id":"PMC_38448574","title":"Guiding the HBO1 complex function through the JADE subunit.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38448574","citation_count":11,"is_preprint":false},{"pmid":"20129050","id":"PMC_20129050","title":"Histone acetylation by HBO1 tightens replication licensing.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20129050","citation_count":11,"is_preprint":false},{"pmid":"39816686","id":"PMC_39816686","title":"Targeting KAT7 inhibits the progression of colorectal cancer.","date":"2025","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/39816686","citation_count":10,"is_preprint":false},{"pmid":"36322781","id":"PMC_36322781","title":"A Therapeutically Targetable NOTCH1-SIRT1-KAT7 Axis in T-cell Leukemia.","date":"2023","source":"Blood cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/36322781","citation_count":10,"is_preprint":false},{"pmid":"34550360","id":"PMC_34550360","title":"The histone acetyltransferase HBO1 promotes efficient tip cell sprouting during angiogenesis.","date":"2021","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34550360","citation_count":8,"is_preprint":false},{"pmid":"32423237","id":"PMC_32423237","title":"LncRNA-KAT7 Negatively Regulates miR-10a Through an Epigenetic Pathway to Participate in Nonsmall Cell Lung Cancer.","date":"2020","source":"Cancer biotherapy & radiopharmaceuticals","url":"https://pubmed.ncbi.nlm.nih.gov/32423237","citation_count":8,"is_preprint":false},{"pmid":"37056143","id":"PMC_37056143","title":"The circular RNA Rap1b promotes Hoxa5 transcription by recruiting Kat7 and leading to increased Fam3a expression, which inhibits neuronal apoptosis in acute ischemic stroke.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/37056143","citation_count":8,"is_preprint":false},{"pmid":"38851533","id":"PMC_38851533","title":"HBO1, a MYSTerious KAT and its links to cancer.","date":"2024","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/38851533","citation_count":7,"is_preprint":false},{"pmid":"27247147","id":"PMC_27247147","title":"Functional analysis of HBO1 in tumor development and inhibitor screening.","date":"2016","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27247147","citation_count":7,"is_preprint":false},{"pmid":"36524217","id":"PMC_36524217","title":"HBO1 as an Important Target for the Treatment of CCL4-Induced Liver Fibrosis and Aged-Related Liver Aging and Fibrosis.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36524217","citation_count":7,"is_preprint":false},{"pmid":"40192836","id":"PMC_40192836","title":"Loss of NgBR causes neuronal damage through decreasing KAT7-mediated RFX1 acetylation and FGF1 expression.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/40192836","citation_count":6,"is_preprint":false},{"pmid":"38421638","id":"PMC_38421638","title":"HBO1 determines SMAD action in pluripotency and mesendoderm specification.","date":"2024","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/38421638","citation_count":6,"is_preprint":false},{"pmid":"35868058","id":"PMC_35868058","title":"KAT7 promoted gastric cancer progression through promoting YAP1 activation.","date":"2022","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/35868058","citation_count":6,"is_preprint":false},{"pmid":"32918898","id":"PMC_32918898","title":"MEAF6 is essential for cell proliferation and plays a role in the assembly of KAT7 complexes.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32918898","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49473,"output_tokens":15226,"usd":0.188405,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":27865,"output_tokens":5448,"usd":0.137763,"stage2_stop_reason":"end_turn"},"total_usd":0.326168,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"HBO1 (KAT7) was identified as a novel protein that physically interacts with the human ORC1 subunit of the origin recognition complex. HBO1 exists as part of a multisubunit complex with histone H3 and H4 acetyltransferase activities, and a fraction associates with ORC1 in human cell extracts.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from human cell extracts, in vitro HAT assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and in vitro HAT assay; foundational paper replicated by many subsequent studies\",\n      \"pmids\": [\"10438470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HBO1 directly interacts with MCM2 via its C2HC zinc finger domain. An N-terminal domain of MCM2 is necessary for binding HBO1, and the C2HC zinc finger of HBO1 is essential for MCM2 binding. A suppressor screen in yeast confirmed the interaction is direct and mediated by the zinc finger.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assays, in vivo co-immunoprecipitation, reverse two-hybrid selection, suppressor mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including genetic suppressor mutagenesis and in vitro reconstitution confirming direct interaction\",\n      \"pmids\": [\"11278932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HBO1 interacts with the androgen receptor (AR) in a ligand-enhanced manner and acts as a transcriptional repressor of AR-mediated transcription. A transcriptional repression domain was mapped to the N-terminal region of HBO1. HBO1 is localized to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, in vitro and in vivo co-immunoprecipitation, immunofluorescence, transient transfection reporter assays, GAL4-DBD mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (co-IP, reporter assay, domain mapping) in a single lab\",\n      \"pmids\": [\"10930412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hbo1 is a positive regulatory factor for pre-replication complex (pre-RC) assembly. Depletion of Hbo1 in human cells caused failure of Mcm2-7 to associate with chromatin even though ORC and Cdc6 loading was normal. Immunodepletion of Xenopus Hbo1 from egg extracts abolished MCM loading and DNA replication, which could be rescued by addition of recombinant Cdt1.\",\n      \"method\": \"siRNA knockdown in human cells, immunodepletion of Xenopus egg extracts, chromatin fractionation, recombinant protein rescue\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complementary human cell and Xenopus egg extract systems with rescue experiment; pathway placement established\",\n      \"pmids\": [\"16428461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HBO1 is a coactivator of the replication licensing factor Cdt1. HBO1 associates with replication origins during G1 phase in a Cdt1-dependent manner, directly interacts with Cdt1, and enhances Cdt1-dependent rereplication. This association is independent of the Cdt1 repressor Geminin.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), rereplication assay, cell-cycle fractionation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed, functional consequence demonstrated, cell-cycle regulation characterized with multiple methods\",\n      \"pmids\": [\"18832067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Plk1 phosphorylates Hbo1 on Ser-57 in vitro and in vivo during mitosis. Cdk1 first phosphorylates Hbo1 on Thr-85/88, creating a docking site for Plk1 recruitment. The Plk1 phosphorylation-defective mutant (S57A) causes G1/S arrest, inhibits MCM chromatin loading, and reduces DNA replication.\",\n      \"method\": \"Yeast two-hybrid, in vitro kinase assay, phospho-specific antibodies, cell-cycle analysis, chromatin fractionation, overexpression of phospho-mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus in vivo phosphorylation and phospho-mutant functional analysis with defined phenotypic readouts\",\n      \"pmids\": [\"18250300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Jade-1/1L is a crucial co-factor that positively regulates HBO1-mediated histone H4 acetylation. PHD fingers of Jade-1/1L are required for nucleosomal H4 acetylation but not for mutual binding. Co-expression of Jade-1/1L and HBO1 synergistically increases H4 acetylation in vivo and in vitro using reconstituted oligonucleosome substrates.\",\n      \"method\": \"Co-immunoprecipitation, in vitro HAT assay with oligonucleosome substrates, siRNA depletion, PHD finger deletion mutants, cell-based H4 acetylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution with nucleosomes plus in vivo corroboration and domain mapping\",\n      \"pmids\": [\"18684714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HBO1 HAT complexes contain PHD finger domains in ING4/5 and JADE1/2/3 subunits that interact with the histone H3 N-terminal tail with distinct specificities toward its methylation status. Their combinatorial action regulates chromatin binding and substrate specificity of HBO1 complexes. HBO1 complexes are enriched throughout gene coding regions, supporting a role in transcription elongation.\",\n      \"method\": \"Biochemical analyses (pulldown, co-IP), genome-wide ChIP analysis, mutant analysis of PHD domains, cell growth assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical, genomic, functional) revealing substrate specificity mechanism\",\n      \"pmids\": [\"19187766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant Hbo1 acetylates nucleosomal histone H4 in vitro, with a preference for lysines 5 and 12. Hbo1 protein is approximately equimolar with active replication origins in normal human fibroblasts.\",\n      \"method\": \"In vitro HAT assay with nucleosomal substrates, semi-quantitative western blot\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay in single study; preference for K5/K12 established biochemically\",\n      \"pmids\": [\"19393168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p53 physically interacts with Hbo1 and negatively regulates its HAT activity in vitro and in cells. Physiological stresses that stabilize p53 (hyperosmotic shock and DNA replication fork arrest) inhibit Hbo1 HAT activity in a p53-dependent manner. Hyperosmotic stress during G1 specifically inhibits MCM2-7 chromatin loading.\",\n      \"method\": \"Co-immunoprecipitation, in vitro HAT assay, siRNA knockdown, chromatin fractionation under stress conditions\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro HAT activity assay plus in vivo epistasis; p53-dependent regulation established with multiple methods\",\n      \"pmids\": [\"17954561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HBO1 HAT activity is essential for DNA replication licensing. A HAT-defective mutant of HBO1 bound at origins cannot load the MCM complex. H4 acetylation at origins is cell-cycle regulated (maximal at G1/S). Geminin inhibits HBO1 acetyltransferase activity in the context of a Cdt1-HBO1 complex and inhibits H4 acetylation and MCM loading in vivo.\",\n      \"method\": \"HAT-defective mutant analysis, ChIP, MCM loading assay, cell-cycle synchronization, Geminin overexpression and co-IP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic mutant establishes requirement for enzymatic activity; Geminin inhibition of complex activity demonstrated biochemically and in vivo\",\n      \"pmids\": [\"20129055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cdt1-induced large-scale chromatin decondensation required for MCM recruitment requires HBO1 HAT activity and histone H4 modifications. HDAC11 inhibits Cdt1-induced chromatin unfolding and MCM loading. This process is regulated positively by Cdt1 and HBO1 in G1 and repressed by Geminin-HDAC11 in S phase.\",\n      \"method\": \"Live-cell chromatin decondensation imaging, HAT-defective mutant, HDAC11 co-immunoprecipitation, MCM loading assay, cell-cycle analysis\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromatin decondensation imaging plus HAT mutant and epistasis analysis in single lab\",\n      \"pmids\": [\"20980834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HBO1 is the major source of histone H3K14 acetylation in vivo during embryonic development. Loss of HBO1 caused >90% reduction in H3K14ac with no significant reduction at other histone residues, developmental arrest at the 10-somite stage, and decreased expression of developmental genes. No defects in DNA replication or cell proliferation were observed in primary fibroblasts from mutant embryos.\",\n      \"method\": \"Conditional knockout mouse model, quantitative western blot for multiple histone marks, gene expression analysis, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with systematic assessment of multiple histone marks identifies H3K14 as primary substrate; negative result for DNA replication also established\",\n      \"pmids\": [\"21149574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Hbo1-Brd1/BRPF2 complex is responsible for global acetylation of H3K14. BRD1 bridges HBO1 and its activator ING4. Depletion of Hbo1 similarly reduces H3K14 acetylation in erythroblasts, and the complex is required for fetal liver erythropoiesis and expression of key erythroid regulator genes including Gata1.\",\n      \"method\": \"Brd1-knockout mouse, biochemical co-immunoprecipitation, genome-wide ChIP mapping, western blot for H3K14ac, forced expression rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO combined with biochemical complex analysis and genome-wide ChIP; H3K14 substrate established in erythroid context\",\n      \"pmids\": [\"21753189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JNK phosphorylates Cdt1 on threonine 29 in response to nongenotoxic stress, leading to rapid dissociation of HBO1 from replication origins and blocking DNA replication initiation. Simultaneously, JNK phosphorylates Jun (AP-1), increasing HBO1 recruitment to stress-response genes. This reciprocal regulation coordinates replication and transcription responses to stress.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibodies, ChIP, mutation of Thr29, DNA replication assay, cell-cycle analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus in vivo ChIP and phospho-mutant analysis; mechanistic switching between replication and transcription roles established\",\n      \"pmids\": [\"21856198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ING4/5 PHD domain association with HBO1-JADE determines the growth inhibitory function of the complex, linked to tumor suppressor activity. HBO1/ING complexes are a major source of H3 and H4 acetylation in vivo. The p53/p21 pathway is a main transcriptional target regulated directly at the p21/CDKN1A initiation site.\",\n      \"method\": \"Molecular dissection of protein domains, co-immunoprecipitation, ChIP, PHD mutant analysis, cell growth assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping plus ChIP and functional analysis in single lab\",\n      \"pmids\": [\"22144582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Plk1 phosphorylation of Hbo1 transcriptionally increases cFos expression and consequently elevates MDR1, conferring gemcitabine resistance in pancreatic cancer. Cells expressing Plk1-unphosphorylatable Hbo1 mutants are more sensitive to gemcitabine.\",\n      \"method\": \"Phospho-mutant overexpression, gene expression analysis, drug sensitivity assays, xenograft mouse model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-mutant analysis with in vivo xenograft validation; single lab\",\n      \"pmids\": [\"23188630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hbo1 is a cyclin E/CDK2 substrate; CDK2 phosphorylates Hbo1 at T88. The low-molecular weight cyclin E (LMW-E)/CDK2 complex phosphorylates Hbo1 at T88 without affecting its HAT activity. Wild-type Hbo1 coexpressed with LMW-E/CDK2 promotes cancer stem-like cell enrichment, whereas the T88A mutant reverses this phenotype.\",\n      \"method\": \"Protein microarray, in vitro kinase assay, phospho-mutant analysis, cancer stem cell (CD44hi/CD24lo) flow cytometry, mammosphere formation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus phospho-mutant functional analysis; single lab\",\n      \"pmids\": [\"23955388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbxw15 directly interacts with HBO1 and mediates its ubiquitination at Lys338 and proteasomal degradation in the cytoplasm. Mek1 triggers HBO1 phosphorylation and degradation, and this process requires Fbxw15. Fbxw15-mediated HBO1 depletion reduces H3K14 acetylation and cellular proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mass spectrometry (Lys338 site), siRNA knockdown, cell proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination site identified by MS, co-IP and functional consequences; single lab\",\n      \"pmids\": [\"23319590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hbo1 promotes proteasome-dependent degradation of estrogen receptor α (ERα) through lysine 48-linked ubiquitination. The acetyltransferase activity of Hbo1 is linked to its ERα ubiquitination activity. Hbo1 depletion increases ERα expression.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, western blot, K48-linked ubiquitin chain analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and depletion phenotype; single lab\",\n      \"pmids\": [\"24125069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"UV damage triggers ATM/ATR-dependent phosphorylation of HBO1 on Ser50 and Ser53, which causes preferential interaction with DDB2 and subsequent ubiquitylation by CRL4DDB2, leading to HBO1 degradation and suppression of cell proliferation. Ser50/53Ala mutants maintain H3K14ac and impair cell-cycle regulation in response to UV.\",\n      \"method\": \"Phospho-specific antibodies, co-immunoprecipitation, ubiquitination assay, CRL4DDB2 reconstitution, phospho-mutant analysis, UV survival assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation sites mapped, E3 ligase identified, phospho-mutant functional analysis; mechanistically comprehensive in single study\",\n      \"pmids\": [\"26572825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRPF3 specifically forms a tetrameric complex with HBO1 (not with related acetyltransferases MOZ, MORF, TIP60, or MOF) and this complex specifically acetylates histone H3K14.\",\n      \"method\": \"Affinity purification, co-immunoprecipitation, western blot for histone marks, LacZ reporter mouse\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex specificity established by co-IP; H3K14 substrate confirmed; single lab\",\n      \"pmids\": [\"26677226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14. BRPF3 and HBO1 are enriched at ORC1-binding sites and replication origins near TSSs. BRPF3 is required for H3K14ac at selected origins and for efficient CDC45 recruitment (origin activation), but not for MCM2-7 loading, defining a distinct licensing-independent role in origin firing.\",\n      \"method\": \"RNAi screen for replication regulators, co-immunoprecipitation, genome-wide ChIP-seq, origin firing assay (CDC45 vs MCM loading by ChIP)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide analysis plus functional dissection distinguishing licensing vs. origin activation steps; orthogonal methods\",\n      \"pmids\": [\"26620551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KAT7 interacts with the CENP-A assembly factor M18BP1. KAT7 knockout in HeLa cells reduces centromeric CENP-A assembly and increases mitotic chromosome misalignment and micronuclei formation. Tethering KAT7 to an ectopic alphoid DNA site removes H3K9me3 and stimulates CENP-A or H3.3 assembly, antagonizing Suv39h1-mediated heterochromatin invasion.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR knockout, immunofluorescence for CENP-A and H3K9me3, tethering assay at ectopic alphoid DNA locus\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus tethering experiment with multiple functional readouts; mechanism of CENP-A assembly competence defined\",\n      \"pmids\": [\"27270040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KAT7 interacts with the N-terminal domain (NTD) of progesterone receptor (PR) in a ligand-dependent manner via its MYST domain and induces SRC-1-dependent coactivation of PR-mediated transcription. HBO1 also interacts with SRC-1a. In HEK293 cells, HBO1 selectively enhances PRB but not PRA transcriptional activity.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transient transfection reporter assays, immunofluorescence, RT-PCR of endogenous target genes\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (yeast 2H, GST pulldown, reporter assay) in single lab; domain mapped\",\n      \"pmids\": [\"16645042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The crystal structure of the HBO1 MYST domain in complex with the N-terminal region of BRPF2 reveals key residues for the HBO1-BRPF2 interaction. The N-terminal region of BRPF2 is sufficient to bind HBO1 and potentiate its HAT activity toward H3K14 (free H3, H4, and nucleosomal H3).\",\n      \"method\": \"Crystal structure determination, in vitro HAT assay, mutagenesis of key interface residues, cell biological validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro enzymatic assay and mutagenesis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28334966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylated HBO1 at CPD (cyclobutane pyrimidine dimer) sites mediates histone acetylation to facilitate XPC recruitment at UV-damaged DNA sites. HBO1 also facilitates accumulation of SNF2H-ACF1 chromatin remodeling complex at CPD sites. HBO1 depletion inhibits CPD repair and sensitizes cells to UV.\",\n      \"method\": \"siRNA knockdown, immunofluorescence at UV-damage sites, co-immunoprecipitation with DDB2, epistasis in XP patient-derived cells, UV survival assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis in XP-patient cells plus localization and functional data; mechanistic order in NER pathway established\",\n      \"pmids\": [\"28719581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hbo1 has intrinsic ubiquitin E3 ligase activity toward ERα. Estradiol-17β inhibits this E3 ligase activity in vitro, while hyperactive ERα mutants from metastatic breast cancers are better substrates for Hbo1-mediated ubiquitination.\",\n      \"method\": \"In vitro ubiquitination assay, Hbo1 knockdown, western blot\",\n      \"journal\": \"Proceedings of the Japan Academy. Series B, Physical and biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro E3 ligase assay in single study; intrinsic E3 activity established biochemically\",\n      \"pmids\": [\"28769019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JADE1 physically links the catalytic HBO1 subunit with its histone H3-H4 substrate. JADE1 increases catalytic efficiency of HBO1 acetylation of H3-H4 substrate ~5-fold through an N-terminal 21-residue HBO1- and histone-binding domain. HBO1 also contains an N-terminal histone-binding domain (HBD) that makes additional H3-H4 contacts but does not significantly contribute to overall HAT activity.\",\n      \"method\": \"In vitro reconstitution with recombinant proteins, kinetic enzyme assays, JADE1 deletion mapping, in vivo validation by deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetic analysis plus in vivo corroboration; mechanism of JADE1-mediated substrate presentation defined\",\n      \"pmids\": [\"29382722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KAT7 mediates H3K14 and H4 acetylation in intragenic regions of EC-enriched genes including VEGFR-2, contributing to RNA polymerase II binding and VEGFR-2 transcription. KAT7 depletion reduces VEGFR-2 expression and disrupts angiogenic potential. KAT7 inhibition in zebrafish disrupts vessel formation, which is rescued by human KAT7.\",\n      \"method\": \"siRNA knockdown, ChIP with tiling array, microarray, KAT7 inhibition in zebrafish embryos, rescue with human KAT7\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus KD phenotype and zebrafish rescue; single lab\",\n      \"pmids\": [\"29414790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LPS elevates HBO1 protein stability by upregulating the deubiquitinase USP25, which associates with HBO1 and suppresses its ubiquitination. Stabilized HBO1 then modulates inflammatory gene transcription in THP-1 monocytes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of USP25, western blot, LPS treatment\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay demonstrating USP25-dependent deubiquitination; single lab\",\n      \"pmids\": [\"30745998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The histone acetyltransferase domain of HBO1 is essential for H3K14 acetylation in AML LSCs. H3K14ac facilitates RNA polymerase II processivity to maintain high expression of HOXA9/HOXA10. A competitive acetyl-CoA analogue inhibitor (WM-3835) inhibits HBO1, recapitulating genetic loss-of-function in AML.\",\n      \"method\": \"CRISPR domain screen, quantitative mass spectrometry, H3K14ac ChIP-seq, RNA pol II ChIP-seq, shRNA screen in LSC model, small-molecule inhibitor characterization (competitive kinetics with acetyl-CoA)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR domain screen, biochemical mechanism of inhibitor action, ChIP-seq, and primary patient AML cells; multiple orthogonal methods across labs\",\n      \"pmids\": [\"31827282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LYAR recruits KAT7 to rDNA loci via BRD2 and BRD4 interactions, resulting in enhanced local acetylation of histone H4 at rDNA, thereby promoting rRNA synthesis. BRD2 is required for KAT7 recruitment; LYAR also binds a BRD4-KAT7 complex that independently promotes H4 and H3 acetylation at rDNA.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-qPCR, siRNA knockdown, rRNA synthesis measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP demonstrate recruitment mechanism; single lab\",\n      \"pmids\": [\"31504794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UHRF1 interacts with methylated H3K14 and thereby suppresses H3K14 acetylation by KAT7, leading to transcriptional repression of the tumor suppressor TUSC3 in colon cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, western blot for H3K14ac\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and co-IP supporting crosstalk between H3K14 methylation and acetylation; single lab\",\n      \"pmids\": [\"31582837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myst2/Kat7 interacts with the tumour suppressor protein Niam (Nuclear Interactor of ARF and Mdm2) in mouse embryonic stem cells, as identified by affinity purification-mass spectrometry. Myst2 forms both H3 and H4 histone acetylation complexes in ESCs similar to those in somatic cells.\",\n      \"method\": \"Affinity purification coupled to mass spectrometry (AP-MS) in mouse ESCs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — AP-MS identifies interaction; limited functional follow-up for the specific Niam interaction in this paper\",\n      \"pmids\": [\"28811661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KAT7 knockout in HeLa and 293T human cells demonstrates that HBO1 is essential for all H3K14ac but is dispensable for H4 acetylation and DNA replication in human cells. Loss of HBO1 and H3K14ac secondarily causes near-complete loss of H4 acetylation after 4 weeks. HBO1 loss principally affects cell adhesion genes.\",\n      \"method\": \"CRISPR/Cas9 knockout, siRNA knockdown in multiple human cell lines, western blot for multiple histone marks, cell proliferation assay, transcriptomic analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO in multiple cell lines with comprehensive histone mark analysis; negative result for H4ac and DNA replication role firmly established\",\n      \"pmids\": [\"31767635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KAT7 loss in AML cells driven by MLL-X fusions leads to rapid and complete loss of both H3K14ac and H4K12ac, reduced proliferation, apoptosis, and differentiation. Loss of these marks causes BRD4 and AF4 to dissociate from MLL-fusion target gene promoters (MEIS1, PBX3, SENP6), implicating acetylated histones as a platform for MLL-fusion adaptor recruitment.\",\n      \"method\": \"Genome-wide CRISPR screen, CRISPR KO, ChIP-seq for histone marks and co-factors, gene expression analysis, differentiation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen followed by ChIP-seq mechanistic analysis; pathway placement established\",\n      \"pmids\": [\"32764680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Protein kinase D1 (PKD1) directly interacts with and phosphorylates KAT7 at Thr97 and Thr331. PKD1-mediated phosphorylation enhances KAT7 stability by reducing ubiquitination-mediated degradation. Phospho-defective mutant KAT7-T97/331A attenuates H4 acetylation, MCM2/6 chromatin loading, DNA replication, and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phospho-mutant analysis, ubiquitination assay, chromatin fractionation, BrdU incorporation\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay and phospho-mutant phenotype; single lab\",\n      \"pmids\": [\"33014433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBO1 is a versatile histone acyltransferase that catalyzes not only histone acetylation but also propionylation, butyrylation, and crotonylation in vivo and in vitro, and does so in a JADE or BRPF scaffold protein-dependent manner. The minimal HBO1/BRPF2 complex accommodates acetyl-CoA, propionyl-CoA, butyryl-CoA, and crotonyl-CoA. HBO1 is the key enzyme for H3K14 acylations at transcription start sites.\",\n      \"method\": \"In vitro acylation assays with different acyl-CoA substrates, in vivo acylation by mass spectrometry, genome-wide ChIP for acylation marks, CBP vs HBO1 comparison with KO cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with multiple acyl-CoA substrates plus genome-wide in vivo corroboration; comprehensive biochemical characterization\",\n      \"pmids\": [\"34259319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Leukemic MLL fusion proteins associate with the HBO1 HAT complex through their trithorax homology domain 2 (THD2) via ING4/5 and PHF16 subunits. MLL-ELL particularly depends on this association for leukemic transformation. HBO1 complex promotes loading of the AF4/ENL/P-TEFb (AEP) complex onto target promoters over EAF1 and p53. The NUP98-HBO1 fusion exerts oncogenic properties via interaction with MLL, not its intrinsic HAT activity.\",\n      \"method\": \"Co-immunoprecipitation in multiple human cell lines, ChIP, leukemic transformation assay in murine hematopoietic progenitors, domain deletion and HAT-dead mutant analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic domain dissection, and functional leukemia transformation assays; HAT-independent mechanism for NUP98-HBO1 established\",\n      \"pmids\": [\"34431785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBO1 is required for H3K14ac throughout the genome in hematopoietic stem cells (HSCs). Loss of HBO1 causes abnormally high recruitment of quiescent HSCs into the cell cycle, leading to HSC pool exhaustion. HBO1 promotes expression of a transcription factor network (Mpl, Tek, Gfi1b, Egr1, Tal1, Gata2, Erg, Pbx1, Meis1, Hox9) essential for HSC quiescence and self-renewal.\",\n      \"method\": \"Conditional KO (Mx1-Cre and Rosa26-CreERT2), competitive transplantation, cell-cycle analysis, H3K14ac ChIP-seq, gene expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary Cre systems, competitive transplantation, ChIP-seq; mechanism established in vivo\",\n      \"pmids\": [\"34724565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HBO1 catalyzes lysine benzoylation (Kbz) in mammalian cells, acting as a 'writer' of this modification. At least 77 HBO1-targeted Kbz sites were identified in the benzoylome, including at chromatin-related proteins.\",\n      \"method\": \"In vitro benzoylation assay, mass spectrometry-based benzoylome analysis in KO cells, western blot\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus KO-based proteomics; single lab\",\n      \"pmids\": [\"36388951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT1 deacetylates KAT7, activating it. SIRT1 loss leads to hyperacetylation of KAT7 and reduced H4K12ac. Overexpression of a non-acetylatable KAT7 mutant partly rescues SIRT1 loss-induced proliferation defects in T-ALL, establishing a NOTCH1-SIRT1-KAT7 regulatory axis.\",\n      \"method\": \"Global acetyl proteomics upon SIRT1 loss, KAT7 non-acetylatable mutant rescue, H4K12ac measurement, gene expression profiling\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetyl proteomics identifies KAT7 acetylation site; non-acetylatable mutant rescue supports mechanism; single lab\",\n      \"pmids\": [\"36322781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT7 mediates the K525 crotonylation of CANX (calnexin). Loss of KAT7 renders MTORC1 insensitive to leucine deprivation. KAT7-mediated CANX K525 crotonylation is required for lysosomal translocation of CANX and subsequent inhibition of Ragulator activity toward RRAG GTPases during leucine deprivation.\",\n      \"method\": \"Cell-free MTORC1 activation system, co-immunoprecipitation, site-specific crotonylation mutagenesis (K525), KAT7 KO, lysosomal fractionation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — non-histone substrate (CANX K525cr) identified with KO and site-specific mutant; single lab\",\n      \"pmids\": [\"35266843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT7 is required for optimal expansion of medullary thymic epithelial cells (mTECs) and for expression of AIRE-dependent peripheral tissue genes (PTGs), associated with enhanced chromatin accessibility at PTG loci. TEC-specific Kat7 deletion leads to organ-specific autoimmunity resembling Aire-deficient mice.\",\n      \"method\": \"Conditional TEC-specific KO, ATAC-seq for chromatin accessibility, gene expression analysis, histological assessment of autoimmunity\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional TEC KO with ATAC-seq mechanistic analysis and in vivo autoimmunity phenotype; pathway position established\",\n      \"pmids\": [\"35061506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HBO1 functions as a lysine lactyltransferase: it catalyzes the addition of lysine lactylation (Kla) in vitro and intracellularly. E508 is a key site for lactyltransferase activity. HBO1 preferentially catalyzes histone H3K9la. Scaffold proteins JADE1 and BRPF2 promote enzymatic activity for histone Kla. H3K9la at TSSs is required for gene transcription.\",\n      \"method\": \"In vitro lactyltransferase assay, E508 mutagenesis, quantitative proteomics of Kla sites in KO cells, site-specific antibodies, CUT&Tag for H3K9la at TSSs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis, quantitative proteomics, and genome-wide CUT&Tag; multiple orthogonal methods in single comprehensive study\",\n      \"pmids\": [\"38670996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT7 is required for neural stem cell plasticity and de novo gene activation. KAT7 and H3K14ac are present at inactive genes, intergenic regions, and in heterochromatin — not only at transcribed genes. KAT7 is not required for continued transcription of already-active genes but is indispensable for activation of repressed genes. Loss of KAT7 abolishes neural stem cell differentiation pathways; re-expression restores developmental potential.\",\n      \"method\": \"Conditional KO, H3K14ac ChIP-seq, gene expression profiling, neural stem cell differentiation assays, KAT7 re-expression rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq and functional rescue; mechanistic distinction between gene maintenance vs. activation established\",\n      \"pmids\": [\"36641753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Identification of histone lysine acetoacetylation (Kacac) as a novel post-translational modification. HBO1, traditionally an acetyltransferase, also serves as an acetoacetyltransferase, adding acetoacetyl groups to histones. 33 Kacac sites on mammalian histones were identified.\",\n      \"method\": \"HPLC co-elution, MS/MS analysis with synthetic peptides, western blot, isotopic labeling, in vitro acetoacetyltransferase assay\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biochemical validation approaches for novel modification; single lab discovery study\",\n      \"pmids\": [\"37382194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HBO1 interacts with SMAD4 and co-binds open chromatin marked by H3K14ac and H3K4me3 in undifferentiated hESCs to maintain pluripotency. Upon BMP4-induced differentiation, HBO1/SMAD4 co-occupy mesoderm gene loci. HBO1-null hESCs fail to respond to TGF-β signaling to maintain pluripotency and cannot form mesendoderm.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq for HBO1 and SMAD4, conditional KO hESCs, differentiation assays (gastruloids, teratomas)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP-seq, and KO hESC functional assays establish mechanistic interaction with TGF-β/SMAD pathway\",\n      \"pmids\": [\"38421638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NLRP11 bridges KAT7 to vimentin, enabling KAT7 to directly acetylate vimentin at Lys104. NLRP11 also induces cytoplasmic localization of KAT7 to facilitate vimentin K104Ac. This acetylation promotes EMT and malignant behavior in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay (KAT7 + vimentin substrate), site-specific K104Q/R mutations, subcellular fractionation, in vivo xenograft\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro acetylation of non-histone substrate validated with co-IP and site-specific mutants; single lab\",\n      \"pmids\": [\"37424170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT7 acetylates H3K14 to enhance MRAS transcription, activating the MAPK/ERK pathway in colorectal cancer. Re-expression of KAT7, but not an acetyltransferase-deficient mutant, rescues MRAS expression and ERK phosphorylation after KAT7 knockdown.\",\n      \"method\": \"shRNA knockdown, CRISPR KO, acetyltransferase-dead mutant rescue, RNA-seq, ChIP-qPCR for H3K14ac at MRAS promoter, ERK phosphorylation western blot\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetyltransferase-dead mutant rescue plus ChIP confirms mechanism; single lab\",\n      \"pmids\": [\"39816686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PZP (PHD1-zinc-knuckle-PHD2) domain of JADE engages the nucleosome through binding to histone H3 and DNA, directing the HBO1 complex to chromatin targets. Recognition of unmethylated H3K4 by PZP directs enzymatic activity toward histone H4 acetylation, whereas H3K4 hypermethylation alters histone substrate selectivity. These structural findings were linked to leukemogenesis via the NUP98-JADE2 fusion.\",\n      \"method\": \"Structural analysis of PZP domain, genomic binding studies (ChIP-seq), complex assembly in vivo, nucleosome-binding assays, leukemic transformation assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structural + biochemical nucleosome binding + genomic + functional leukemia assay; mechanism of complex recruitment and substrate selectivity established\",\n      \"pmids\": [\"38448574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT7 crotonylation at K432 (facilitated by hMOF) competes against its acetylation (regulated by HDAC2) at the same residue upon DNA damage. This competition reduces HBO1 histone acetyltransferase activity, leading to decreased H3K14ac at procentriole formation gene promoters and inhibition of procentriole formation.\",\n      \"method\": \"Site-specific K432 crotonylation/acetylation mutants, in vitro HAT assay, co-IP with hMOF/HDAC2, ChIP-qPCR for H3K14ac, procentriole formation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assay with site-specific mutants plus ChIP and functional procentriole assay; competitive modification mechanism established\",\n      \"pmids\": [\"40064919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KAT7 and KAT6A associate with NUP98 fusion oncoproteins on chromatin and within phase-separated condensates via the common subunit BRPF1. Genetic inactivation or pharmacologic inhibition of KAT7 decreases global H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and leads to myeloid differentiation. KAT6A/7 inhibition is efficacious in menin inhibitor-resistant NUP98-rearranged leukemia.\",\n      \"method\": \"CRISPR genetic inactivation, pharmacologic inhibition, ChIP-seq for H3K23ac and NUP98 fusion, co-IP, in vivo xenograft mouse models, synergy analysis with menin inhibitor\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq mechanistic analysis, co-IP, multiple in vivo xenograft models, and drug combination testing; comprehensive study\",\n      \"pmids\": [\"40536430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of KAT7 suppresses KAT7-mediated acetylation of the transcriptional repressor RFX1, stabilizing RFX1 (by blocking its proteasomal degradation) and thereby suppressing FGF1 transcription, leading to neuronal damage. NgBR regulates this axis by controlling KAT7 expression.\",\n      \"method\": \"RNA sequencing, co-immunoprecipitation (KAT7-RFX1 interaction), KAT7 KO, western blot for RFX1 stability, FGF1 transcription analysis, neuronal apoptosis assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and KO with defined substrate and functional consequence; single lab, non-histone substrate\",\n      \"pmids\": [\"40192836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT7 acetylates LDHA at lysine 118 in head and neck squamous carcinoma (HNSCC), enhancing LDHA activity and upregulating LDHA protein expression, thereby promoting the Warburg effect and tumor proliferation/metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, site-specific K118 mutation, lactate production assay, KAT7 KO/OE with LDHA rescue, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro acetylation assay with site-specific mutant plus functional metabolic readout; single lab, non-histone substrate\",\n      \"pmids\": [\"38593918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MEAF6 modulates KAT7 complex assembly; in the absence of MEAF6, KAT7 increases its ability to interact with PHD-finger proteins (Brpfs/Jades). MEAF6 is essential for cell proliferation but not for HAT activity itself.\",\n      \"method\": \"Inducible Meaf6 KO in mouse ES cells, co-immunoprecipitation, histone acetylation western blot, cell proliferation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus co-IP establishing modulatory role in complex assembly; single lab\",\n      \"pmids\": [\"32918898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRPF3-mediated degradation pathway: the E3 ligase HUWE1 mediates ubiquitin-dependent degradation of Myst2/KAT7, and BRPF3 antagonizes HUWE1-mediated Myst2 degradation by direct protein-protein interaction, retaining Myst2 stability. This balance is required for normal differentiation and cell-cycle progression in embryonic stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, BRPF3/HUWE1 overexpression/KD, Myst2 stability western blot, ESC differentiation assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ubiquitination assay establishing HUWE1 as E3 ligase and BRPF3 as antagonist; single lab\",\n      \"pmids\": [\"32555450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HBO1 inhibits NF-κB activity by coactivator sequestration (squelching), not by binding p65/RelA or disrupting NF-κB DNA binding. The N-terminal serine-rich region of HBO1 (not its acetyltransferase domain) is required for this inhibitory activity.\",\n      \"method\": \"Reporter gene assay, EMSA, NF-κB component overexpression, N-terminal deletion mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with negative EMSA result and functional reporter assay; single lab\",\n      \"pmids\": [\"16997280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FAD24 interacts with HBO1 and recruits it to origins of DNA replication during late mitosis (when the pre-RC is assembled). When fad24 is knocked down, recruitment of HBO1 to origins is reduced, impairing mitotic clonal expansion during adipogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at replication origins, siRNA knockdown, colocalization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP demonstrating FAD24-dependent recruitment to origins; single lab\",\n      \"pmids\": [\"18029353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HBO1 promotes angiogenic tip cell sprouting through maintaining H3K14ac and appropriate gene expression in endothelial cells. Loss of HBO1 impairs developmental sprouting angiogenesis; single-cell RNA-seq reveals increased tip cell abundance and overcrowding in the sprouting front.\",\n      \"method\": \"Endothelial-specific conditional KO, retinal wholemount imaging, single-cell RNA-seq, H3K14ac ChIP-seq\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with single-cell RNA-seq and genome-wide ChIP-seq; mechanistic basis for tip cell regulation established\",\n      \"pmids\": [\"34550360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT7/HBO1/MYST2 is a MYST-family lysine acetyltransferase that exists in two principal tetrameric complexes—one containing JADE1/2/3 scaffold proteins (which directs H4K5/8/12 acetylation) and one containing BRPF1/2/3 scaffold proteins (which directs H3K14 acetylation)—and it is the major cellular source of H3K14 acetylation in vivo; it functions as a coactivator of the replication licensing factor Cdt1 by acetylating histone H4 at origins to facilitate MCM2-7 loading, is regulated by cell-cycle kinases (Cdk1, Plk1, PKD1) through phosphorylation that modulates its stability and activity, is degraded after DNA damage via CRL4DDB2-mediated ubiquitination (dependent on ATM/ATR phosphorylation), and beyond histones catalyzes acylation of non-histone substrates including calnexin K525cr, LDHA K118ac, vimentin K104ac, and RFX1, while also acting as an E3 ubiquitin ligase for ERα; at the genomic level, KAT7-dependent H3K14ac is a prerequisite for de novo gene activation (but not maintenance of ongoing transcription), centromere integrity (by antagonizing Suv39h1-mediated H3K9me3), AIRE-dependent peripheral tolerance gene expression in thymic epithelial cells, HSC quiescence and self-renewal, and is co-opted by oncogenic MLL-fusion proteins and NUP98-fusion proteins to maintain leukemia stem cell transcriptional programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAT7 (HBO1/MYST2) is a MYST-family lysine acetyltransferase that operates as the catalytic engine of multisubunit chromatin-modifying complexes and is the major cellular source of histone H3K14 acetylation in vivo [#12, #35]. Its substrate specificity and chromatin targeting are dictated by mutually exclusive scaffold subunits: JADE1/2/3 directs acetylation toward histone H4 (K5/K12), while BRPF1/2/3 directs activity toward H3K14, with ING4/5 and the PHD/PZP modules of these partners reading the H3 tail to govern recruitment and substrate choice [#6, #7, #13, #21, #51]. Structural and kinetic studies show JADE1 presents the H3-H4 substrate to the MYST domain to boost catalytic efficiency, and a defined BRPF2-MYST interface potentiates H3K14 activity [#25, #28]. Beyond acetylation, the same enzyme is a versatile acyltransferase that installs propionyl, butyryl, crotonyl, benzoyl, acetoacetyl, and lactyl marks in a scaffold-dependent manner, with H3K14 acylation and H3K9 lactylation at transcription start sites required for gene transcription [#38, #41, #45, #47]. Functionally, KAT7-dependent H3K14ac is a prerequisite for de novo activation of repressed genes rather than maintenance of ongoing transcription, underlies neural and embryonic stem cell plasticity, hematopoietic stem cell quiescence and self-renewal, AIRE-dependent peripheral tolerance gene expression in thymic epithelium, and centromere integrity through antagonism of Suv39h1-mediated H3K9me3 to license CENP-A assembly [#23, #40, #44, #46, #48]. In its earliest-characterized role KAT7 acts as a coactivator of the licensing factor Cdt1, acetylating histone H4 at origins to drive chromatin decondensation and MCM2-7 loading, a function gated by p53, Geminin, and cell-cycle kinases [#3, #4, #10]. KAT7 stability and activity are tightly controlled by phosphorylation (Cdk1/Plk1, CDK2, PKD1, JNK, ATM/ATR), competing acyl modifications, deacetylation by SIRT1, and ubiquitin ligases (CRL4DDB2, Fbxw15, HUWE1) opposed by deubiquitinase USP25 and the stabilizing partner BRPF3 [#5, #14, #20, #30, #37, #42, #57]. KAT7 also acetylates non-histone substrates including calnexin K525cr (mTORC1 signaling), LDHA K118 (the Warburg effect), vimentin K104 (EMT), and RFX1, and is co-opted by oncogenic MLL-fusion and NUP98-fusion proteins to sustain leukemia stem cell transcriptional programs, making it a therapeutic target in AML [#31, #36, #39, #43, #49, #53, #55].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established KAT7 as a chromatin-associated acetyltransferase physically tied to the replication machinery, framing it as a candidate link between histone modification and origin function.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and in vitro HAT assay identifying HBO1 as an ORC1-interacting protein with H3/H4 acetyltransferase activity\",\n      \"pmids\": [\"10438470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show whether HAT activity is required at origins\", \"Complex composition and scaffold subunits unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined a direct, domain-specific physical bridge between KAT7 and the MCM helicase, anchoring it mechanistically to pre-replication complex components.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, suppressor mutagenesis mapping MCM2 binding to the HBO1 C2HC zinc finger\",\n      \"pmids\": [\"11278932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MCM2 binding for replication not yet tested\", \"Did not implicate acetylation activity\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed KAT7 functionally upstream of MCM loading, showing it is required for pre-RC assembly downstream of ORC/Cdc6.\",\n      \"evidence\": \"siRNA in human cells and immunodepletion of Xenopus egg extracts with recombinant Cdt1 rescue and chromatin fractionation\",\n      \"pmids\": [\"16428461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether enzymatic activity versus scaffolding drives MCM loading\", \"Histone substrate at origins not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified KAT7 as a Cdt1 coactivator and revealed cell-cycle kinase control of its replication function, integrating it into G1/S licensing regulation.\",\n      \"evidence\": \"Co-IP, ChIP, rereplication assays for Cdt1 interaction; in vitro/in vivo kinase assays and phospho-mutants for Cdk1-primed Plk1 phosphorylation at Ser57\",\n      \"pmids\": [\"18832067\", \"18250300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation alters complex composition not resolved\", \"Direct origin acetyl substrate still inferred\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that KAT7 catalytic activity, not just binding, is essential for replication licensing via H4 acetylation-driven chromatin decondensation, and is restrained by Geminin and p53.\",\n      \"evidence\": \"HAT-defective mutants, ChIP, MCM loading assays, Geminin co-IP, live-cell decondensation imaging, and p53-dependent HAT inhibition assays\",\n      \"pmids\": [\"20129055\", \"20980834\", \"17954561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of H4 acetylation versus other marks at origins unclear\", \"Crosstalk between p53 and Geminin regulation not integrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the scaffold logic dividing KAT7 activity into JADE-directed H4 acetylation and BRPF-directed H3K14 acetylation, and assigned KAT7 as the principal in vivo source of H3K14ac.\",\n      \"evidence\": \"JADE1 PHD reconstitution HAT assays, Brd1/BRPF2 KO mouse with genome-wide ChIP, and a conditional Hbo1 KO mouse profiling multiple histone marks\",\n      \"pmids\": [\"18684714\", \"21753189\", \"21149574\", \"19187766\", \"19393168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of scaffold-imposed specificity not yet solved at this stage\", \"Why H3K14ac loss arrests development mechanistically undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Distinguished a licensing-independent role for the HBO1-BRPF3 complex in origin firing and uncovered DNA-damage-triggered destruction of KAT7, linking it to genome surveillance.\",\n      \"evidence\": \"RNAi screen, ChIP-seq, and CDC45-versus-MCM assays for BRPF3; ATM/ATR phospho-site mapping (Ser50/53) with CRL4DDB2 reconstitution for damage-induced degradation\",\n      \"pmids\": [\"26620551\", \"26677226\", \"26572825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single enzyme partitions between licensing and firing roles unresolved\", \"In vivo relevance of damage-induced degradation to repair outcomes incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided structural definition of the BRPF2-MYST interface and JADE1-mediated substrate presentation, and positioned KAT7 in nucleotide excision repair chromatin remodeling.\",\n      \"evidence\": \"Crystal structure of MYST-BRPF2 with HAT assays and mutagenesis; kinetic reconstitution of JADE1-stimulated catalysis; UV-damage localization and XP-cell epistasis for NER\",\n      \"pmids\": [\"28334966\", \"29382722\", \"28719581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full holocomplex structure not determined\", \"Relative importance of NER role versus replication role in vivo unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established KAT7's role in centromere maintenance by enabling CENP-A assembly through antagonism of Suv39h1 heterochromatin, broadening its function beyond replication and transcription.\",\n      \"evidence\": \"Co-IP with M18BP1, CRISPR KO with CENP-A/H3K9me3 immunofluorescence, and ectopic tethering at alphoid DNA\",\n      \"pmids\": [\"27270040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether centromeric function requires a specific scaffold complex not defined\", \"Direct acetyl substrate at centromeres not pinpointed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Decoupled KAT7's histone substrates in human cells, showing it is essential for all H3K14ac but dispensable for replication, overturning the obligatory licensing role and refocusing on transcriptional output.\",\n      \"evidence\": \"CRISPR KO in multiple human cell lines with comprehensive histone-mark westerns and transcriptomics, plus complex-assembly studies of MEAF6 and HUWE1/BRPF3-controlled stability\",\n      \"pmids\": [\"31767635\", \"32918898\", \"32555450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with earlier Xenopus/human replication-licensing data not fully explained\", \"Cell-type dependence of replication role unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined KAT7 as a stem-cell and tolerance regulator that activates gene programs through genome-wide H3K14ac, and expanded its catalytic repertoire to non-acetyl acylations and non-histone substrates.\",\n      \"evidence\": \"Conditional KO with transplantation and ChIP-seq in HSCs; TEC-specific KO with ATAC-seq for AIRE-dependent genes; in vitro acylation and proteomics for crotonyl/benzoyl marks; CANX K525cr mTORC1 system\",\n      \"pmids\": [\"34724565\", \"35061506\", \"38670996\", \"36388951\", \"35266843\", \"36322781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single enzyme selects among diverse acyl-CoA cosubstrates in vivo unclear\", \"Physiological abundance of rarer acylations uncertain\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Crystallized the principle that KAT7/H3K14ac licenses de novo gene activation rather than maintenance, and connected the complex to pluripotency and signaling pathways.\",\n      \"evidence\": \"Conditional KO with ChIP-seq and rescue in neural stem cells; HBO1-SMAD4 co-IP/ChIP-seq in hESCs with differentiation assays; lactyl/acetoacetyl transferase characterization\",\n      \"pmids\": [\"36641753\", \"38421638\", \"38670996\", \"37382194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing activatable from maintained genes not fully defined\", \"Whether acylation marks (lactyl) drive distinct gene programs unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated KAT7 as a therapeutic target in fusion-driven leukemias, showing oncogenic MLL- and NUP98-fusions co-opt the KAT7 complex and its acetyl marks to sustain leukemia stem cell programs.\",\n      \"evidence\": \"CRISPR screens, ChIP-seq for histone marks and fusion proteins, co-IP via BRPF1, small-molecule HBO1 inhibitors, and xenograft/menin-inhibitor combination studies\",\n      \"pmids\": [\"31827282\", \"32764680\", \"34431785\", \"40536430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window between leukemic dependence and normal HSC requirement not defined\", \"Relative contribution of H3K14ac, H4K12ac, and H3K23ac to fusion recruitment varies between studies\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KAT7 integrates its many regulatory inputs (competing acylations at K432, phosphorylation, deacetylation, scaffold choice) to select among histone and non-histone substrates in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking PTM state to substrate/scaffold selection\", \"Quantitative hierarchy of competing acyl-CoA cosubstrates in vivo unknown\", \"Structure of full holocomplex on nucleosome not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [8, 12, 13, 25, 28, 38, 41, 45, 47, 49, 55]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [43, 49, 50, 54, 55]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [19, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 24, 46, 48]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 28, 51]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 24]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [4, 23]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 49]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 13, 35, 38, 46]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [46, 48, 50, 45]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [3, 4, 10, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [31, 36, 39, 53]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 23, 52]}\n    ],\n    \"complexes\": [\n      \"HBO1-JADE complex\",\n      \"HBO1-BRPF complex\",\n      \"ORC/pre-replication complex (associated)\"\n    ],\n    \"partners\": [\n      \"JADE1\",\n      \"BRPF2\",\n      \"BRPF3\",\n      \"ING4\",\n      \"MCM2\",\n      \"CDT1\",\n      \"ORC1\",\n      \"MEAF6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}