{"gene":"KAT8","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"hMOF (KAT8) is a histone H4 lysine 16-specific acetyltransferase required for bulk H4K16 acetylation in mammalian cells. Knockdown of hMOF in HeLa and HepG2 cells causes dramatic reduction of H4K16ac (confirmed by Western blot and mass spectrometry). hMOF and hMSL3 form a complex in mammalian cells. hMOF-depleted cells accumulate in G2/M and show impaired DNA damage repair response to ionizing radiation, with increased phospho-ATM and γH2AX foci.","method":"siRNA knockdown, Western blot, mass spectrometric analysis of endogenous histones, co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry validation, multiple orthogonal methods, independently replicated across multiple labs","pmids":["16024812"],"is_preprint":false},{"year":2005,"finding":"hMOF interacts with ATM protein, and hMOF-dependent H4K16ac is required for ATM autophosphorylation, ATM kinase activity, and downstream effector phosphorylation after ionizing radiation. Blocking H4K16ac increase (via dominant-negative hMOF or siRNA) decreases ATM function and DNA repair while increasing cell killing.","method":"Co-immunoprecipitation, dominant-negative mutant expression, siRNA knockdown, kinase assays, immunofluorescence","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, dominant-negative and RNAi approaches, replicated with multiple methods in one study","pmids":["15923642"],"is_preprint":false},{"year":2008,"finding":"Mof (KAT8) is essential for embryonic development past the blastocyst stage in mice. Mof-null embryos fail to acetylate H4K16 but have normal acetylation of other histone lysine residues, demonstrating non-redundant and specific function. Loss of Mof causes abnormal chromatin aggregation preceding caspase-3 activation and DNA fragmentation.","method":"Conditional knockout mouse model, immunofluorescence, Western blot, caspase-3 assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific phenotypic readout, multiple orthogonal methods, in vivo validation","pmids":["18541669"],"is_preprint":false},{"year":2013,"finding":"Autophagy induction leads to downregulation of hMOF, causing reduction of H4K16ac, which is associated predominantly with downregulation of autophagy-related genes. Antagonizing H4K16ac downregulation during autophagy induction promotes cell death, establishing a feedback loop where H4K16ac levels determine the survival vs. death outcome of autophagy.","method":"Western blot, genome-wide ChIP-seq, siRNA knockdown, cell viability assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, multiple orthogonal methods, published in Nature with rigorous controls","pmids":["23863932"],"is_preprint":false},{"year":2016,"finding":"KAT8/MOF and a subset of its NSL complex partners reside in mitochondria in addition to the nucleus. Mitochondrial MOF binds mtDNA (dependent on KANSL3) and regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA. A catalytically deficient MOF mutant fails to rescue respiratory and mtDNA transcriptional defects, indicating catalytic activity is required.","method":"Subcellular fractionation, ChIP, conditional knockout mouse model (cardiac), RNA-seq, catalytic mutant rescue experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — fractionation, ChIP, catalytic mutant rescue, in vivo knockout with defined phenotype; multiple orthogonal methods","pmids":["27768893"],"is_preprint":false},{"year":2021,"finding":"KAT8 exhibits complex-dependent catalytic activity: as part of the NSL complex it catalyzes H4K5ac and H4K8ac, whereas as part of the MSL complex it catalyzes the bulk of H4K16ac. MSL complex proteins and H4K16ac are not required for cell proliferation and chromatin accessibility, whereas the NSL complex is essential for cell survival by stimulating transcription initiation at housekeeping gene promoters.","method":"Auxin-inducible degron system for protein depletion, mass spectrometry, ATAC-seq, RNA-seq, ChIP-seq","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical fractionation, mass spectrometry, multiple genome-wide assays, rigorous controls with depletion system","pmids":["33657400"],"is_preprint":false},{"year":2012,"finding":"SIRT1 deacetylates the enzymatic (MYST) domains of hMOF and TIP60, inhibiting their acetyltransferase activity and promoting ubiquitination-dependent degradation. Immediately following DNA damage, SIRT1 binding to hMOF is transiently interrupted with corresponding hMOF hyperacetylation. Lysine-to-arginine mutations at SIRT1-targeted lysines on hMOF repress DNA double-strand break repair and inhibit apoptosis induction.","method":"Co-immunoprecipitation, in vitro deacetylation assay, mutagenesis, ubiquitination assay, DNA damage repair assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro assay, mutagenesis, reciprocal Co-IP, multiple orthogonal methods in one study","pmids":["22586264"],"is_preprint":false},{"year":2011,"finding":"hMOF undergoes autoacetylation in vitro and in vivo, restricted to the MYST domain with K274 as the major autoacetylation site. SIRT1 interacts with the MYST domain of hMOF and deacetylates it. Non-acetylated hMOF binds nucleosomes more robustly; acetylation decreases nucleosome binding. SIRT1 deacetylation of hMOF promotes its chromatin recruitment and H4K16ac activity.","method":"In vitro acetylation assay, co-immunoprecipitation, in vitro nucleosome binding assay, ChIP, siRNA knockdown","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, nucleosome binding assay, ChIP; multiple methods in one study","pmids":["21502975"],"is_preprint":false},{"year":2016,"finding":"Structural and mutational analysis of hMOF K274 autoacetylation reveals that all amino acid substitutions at K274 result in significant destabilization of hMOF and complete loss of catalytic activity toward histone H4. X-ray crystal structure of K274P mutant shows disordering of the α2-β7 loop harboring K274, explaining loss of function. K274 autoacetylation (driven by Ac-CoA binding) is required for hMOF stability and cognate substrate acetylation.","method":"X-ray crystallography, mutagenesis, in vitro acetyltransferase assay, stability measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro assay, multiple orthogonal methods","pmids":["27382063"],"is_preprint":false},{"year":2015,"finding":"KAT8 follows a ping-pong kinetic mechanism in which Ac-CoA binds first, followed by the histone substrate. This was confirmed by isothermal titration calorimetry (ITC) affinity measurements of both substrates. Anacardic acid inhibits KAT8 via this mechanism and the inhibition constants of anacardic acid derivatives were calculated.","method":"Enzyme kinetics, isothermal titration calorimetry (ITC), inhibitor assays","journal":"European journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic mechanism established by kinetics and ITC, single lab but multiple orthogonal methods","pmids":["26505788"],"is_preprint":false},{"year":2019,"finding":"KAT8 directly interacts with IRF3 via its MYST domain and mediates IRF3 acetylation at lysine 359, inhibiting IRF3 recruitment to IFN-I gene promoters and decreasing its transcriptional activity. KAT8 deficiency in mice protects from viral challenge by enhancing IFN-I production.","method":"Co-immunoprecipitation, in vitro acetylation assay, ChIP, siRNA screen, mouse viral challenge model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro acetylation assay, Co-IP, ChIP, in vivo mouse model; multiple orthogonal methods","pmids":["30842237"],"is_preprint":false},{"year":2023,"finding":"In response to IFNγ, KAT8 undergoes phase separation with IRF1 and forms biomolecular condensates, which promotes IRF1 K78 acetylation and its binding to the PD-L1 (CD274) promoter, enriching transcription apparatus and upregulating PD-L1 mRNA. Multivalency from specific and promiscuous IRF1-KAT8 interactions is required for condensate formation. A blocking peptide (2142-R8) that disrupts KAT8-IRF1 condensate formation inhibits PD-L1 expression and enhances antitumor immunity.","method":"Phase separation assays, Co-immunoprecipitation, in vitro acetylation assay, ChIP, blocking peptide experiments, in vivo tumor models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, in vitro assay, ChIP, in vivo validation, multiple orthogonal methods","pmids":["36894639"],"is_preprint":false},{"year":2014,"finding":"hMOF physically interacts with Nrf2 and acetylates it at Lys588. MOF-mediated acetylation increases nuclear retention of Nrf2 and transcription of its downstream genes. MOF/hMOF is essential for anti-oxidative and anti-drug responses in an Nrf2-dependent manner.","method":"Co-immunoprecipitation, in vitro acetylation assay, nuclear fractionation, siRNA knockdown, reporter assay, mouse xenograft","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, fractionation, in vivo validation; multiple methods in one study","pmids":["24571482"],"is_preprint":false},{"year":2013,"finding":"hMOF (KAT8) is responsible for acetylation of DBC1/CCAR2 at K112 and K215. Acetylation of these residues inhibits DBC1-SirT1 binding and increases SirT1 deacetylase activity. After DNA damage, ATM-dependent inhibition of hMOF binding to DBC1 leads to DBC1 deacetylation and increased SirT1-DBC1 binding. A DBC1 acetylation-mimic mutant fails to promote apoptosis after DNA damage.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, DNA damage assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, mutagenesis; multiple methods in one study","pmids":["24126058"],"is_preprint":false},{"year":2016,"finding":"MOF acetyltransferase interacts with LSD1 and is responsible for acetylation of LSD1 in epithelial cells. Acetylation of LSD1 reduces its association with nucleosomes, increasing H3K4 methylation at LSD1 target genes and activating transcription. MOF expression is downregulated by EMT-inducing signals, and MOF depletion enhances EMT and tumor metastasis.","method":"Co-immunoprecipitation, in vitro acetylation assay, nucleosome association assay, ChIP, siRNA knockdown","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, ChIP; multiple orthogonal methods","pmids":["27292636"],"is_preprint":false},{"year":2011,"finding":"SUV420H2-mediated H4K20me3 and hMOF-mediated H4K16ac play opposing roles in RNA Pol II promoter-proximal pausing. H4K16ac promotes release of Pol II from pausing through recruitment of BRD4 and pTEFb. H4K20me3 blocks Pol II escape by locally inhibiting H4K16ac. Combined inhibition of H4K20me3 and DNA methylation results in re-recruitment of hMOF, H4K16ac, and synergistic reactivation of gene expression.","method":"ChIP, siRNA knockdown, inhibitor treatments, reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP experiments, siRNA knockdown, multiple gene targets tested","pmids":["21321083"],"is_preprint":false},{"year":2014,"finding":"MOF (MSL complex) specifically regulates Tsix, the major repressor of Xist lncRNA, in mouse embryonic stem cells. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently enhanced Xist accumulation and variable X-chromosome inactivation during differentiation. The NSL complex provides additional Tsix-independent repression of Xist by maintaining pluripotency.","method":"ChIP-seq, RNA-seq, siRNA knockdown, allele-specific analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, RNA-seq, genetic depletion with specific phenotypic readout","pmids":["24842875"],"is_preprint":false},{"year":2021,"finding":"TGFβ activates autophagy via SMAD3-dependent downregulation of MYST1 (KAT8), which regulates expression of core autophagy components ATG7 and BECLIN1 via H4K16 acetylation. Autophagy activation in fibroblasts promotes collagen release and is required to induce tissue fibrosis. Forced expression of MYST1 abrogates TGFβ-stimulated autophagy.","method":"ChIP, siRNA knockdown, overexpression, mouse fibrosis models, Western blot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, genetic rescue, in vivo mouse models; multiple orthogonal methods, replicated across fibrosis models","pmids":["34285225"],"is_preprint":false},{"year":2023,"finding":"MOF (via its KANSL complex) acetylates COX17, a complex IV assembly factor, at a specific residue. Loss of MOF-KANSL complex leads to mitochondrial fragmentation, reduced cristae density, and impaired electron transport chain complex IV integrity. Expression of acetylation-mimetic COX17 rescues these defects even in the absence of MOF, demonstrating that COX17 acetylation is a critical downstream effector of MOF in mitochondrial physiology.","method":"Co-immunoprecipitation, in vitro acetylation assay, mitochondrial fractionation, electron microscopy, acetylation-mimetic mutant rescue experiments, patient fibroblasts","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro acetylation, Co-IP, structural imaging, acetylation mimic rescue; multiple orthogonal methods, patient-derived validation","pmids":["37813994"],"is_preprint":false},{"year":2024,"finding":"KAT8 acts as a pan-lactyltransferase (Kla writer) capable of installing lysine lactylation on multiple protein substrates. KAT8 specifically lactylates eEF1A2 at K408, boosting translation elongation and protein synthesis contributing to colorectal cancer tumorigenesis. Deletion of KAT8 inhibited CRC tumor growth, especially in high-lactic tumor microenvironments.","method":"Proteomics/lactylome profiling, co-immunoprecipitation, in vitro lactylation assay, KAT8 deletion mouse models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro lactylation assay, proteomics, Co-IP, in vivo genetic deletion; multiple orthogonal methods","pmids":["38359291"],"is_preprint":false},{"year":2017,"finding":"MOF HAT activity is required for MLL-AF9-driven leukemogenesis. Conditional deletion of Mof in MLL-AF9 mouse leukemia model reduced tumor burden and prolonged survival. Rescue experiments with catalytically inactive MOF mutants showed enzymatic activity is required for cancer pathogenicity. MOF loss impaired global H4K16ac and increased γH2AX foci.","method":"Conditional knockout mouse model, catalytic mutant rescue experiments, RNA-seq, immunofluorescence","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model, catalytic mutant rescue, multiple cancer models tested","pmids":["28202522"],"is_preprint":false},{"year":2017,"finding":"KAT8 is essential for mouse oocyte development. Oocyte-specific deletion of Kat8 causes female infertility with follicle development failure. KAT8 deficiency results in significant downregulation of antioxidant genes with consequent ROS increase, which can be rescued by N-acetylcysteine. ChIP assays show KAT8 directly binds promoter regions of antioxidant genes.","method":"Conditional knockout (Gdf9-Cre), RNA-seq, ChIP, antioxidant rescue experiments (N-acetylcysteine injection)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional knockout, ChIP, pharmacological rescue; multiple orthogonal methods","pmids":["28506985"],"is_preprint":false},{"year":2020,"finding":"MOF regulates erythropoiesis by dynamic chromatin recruitment; its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator necessary and sufficient for cell-type-specific induction of Mof expression. Mof-depleted HSC plasticity can be rescued by downstream effector GATA1 or HDAC inhibitor-mediated rebalancing of acetylation.","method":"Single-cell RNA-seq, ChIP-seq, genetic rescue experiments, HDAC inhibitor treatment","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — scRNA-seq, ChIP-seq, genetic rescue; multiple methods in one study","pmids":["32671208"],"is_preprint":false},{"year":2014,"finding":"MYST1 (KAT8) co-stimulates androgen receptor (AR) and NF-κB functions in prostate cancer cells. NF-κB activation promotes SIRT1-mediated deacetylation of MYST1, and mutually exclusive interactions of MYST1 with SIRT1 vs. AR regulate H4K16ac. MYST1 depletion in AR-lacking cells triggers PARP/caspase-3 cleavage (apoptosis), while in AR-transformed cells it induces CDK N1A/p21 and G2M arrest.","method":"Co-immunoprecipitation, siRNA knockdown, ChIP, cell cycle analysis, Western blot","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ChIP, knockdown; single lab with multiple methods but limited reconstitution","pmids":["24702180"],"is_preprint":false},{"year":2016,"finding":"KAT8 colocalizes with WDR5 at androgen receptor (AR) target genes. PKN1/H3T11 phosphorylation leads to WDR5/MLL methyltransferase recruitment, which then recruits KAT8 to effect H4K16ac and AR-dependent gene activation. KAT8 knockdown significantly decreased AR target gene expression and prostate cancer cell proliferation.","method":"ChIP, siRNA knockdown, Co-immunoprecipitation, gene expression analysis","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, and knockdown; single lab, multiple methods","pmids":["27268279"],"is_preprint":false},{"year":2016,"finding":"TET1 forms a chromatin complex with hMOF and Sin3a in mouse embryonic stem cells. TET1 facilitates chromatin affinity and enzymatic activity of hMOF toward H4K16ac by preventing hMOF autoacetylation, thereby regulating expression of downstream genes including DNA repair genes. Tet1 knockout cells show DNA damage accumulation and genomic instability.","method":"Co-immunoprecipitation, ChIP-seq analysis (integrative genomics), in vitro biochemical studies, Tet1 knockout MEF cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro biochemistry, ChIP-seq integration; single lab with multiple methods","pmids":["27733505"],"is_preprint":false},{"year":2018,"finding":"MOF interacts with PCNA at replication forks and affects PCNA ubiquitination and recruitment to DNA damage sites. MOF depletion in cells under replicative stress decreases replication fork speed, increases stalled replication forks, promotes new origin firing, and increases R-loop formation. MOF depletion also compromises DNA end resection and CHK1 phosphorylation.","method":"Co-immunoprecipitation, DNA fiber assay, PCNA ubiquitination assay, immunofluorescence, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, DNA fiber assay, ubiquitination assay; single lab with multiple methods","pmids":["29298824"],"is_preprint":false},{"year":2020,"finding":"WSTF lysine 426 is acetylated by MOF (via MSL1v1-mediated interaction) and deacetylated by SIRT1. WSTF K426 acetylation promotes WSTF Ser158 phosphorylation, enhancing WSTF kinase and transcriptional regulatory activity and cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, cell proliferation and invasion assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro acetylation assay, Co-IP, mutagenesis; single lab","pmids":["32518374"],"is_preprint":false},{"year":2024,"finding":"USP10 (a deubiquitinase) binds to and deubiquitinates MOF at lysine 410, protecting it from proteasome-dependent degradation. MOF stabilization by USP10 promotes H4K16ac enrichment at the ANXA2 promoter (in a JUN-dependent manner), stimulating ANXA2 transcription and activating Wnt/β-Catenin signaling to facilitate esophageal cancer progression. Catalytically inactive MOF-E350Q fails to promote progression.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, catalytic mutant rescue, siRNA knockdown, in vivo tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, catalytic mutant; multiple orthogonal methods in one study","pmids":["38317006"],"is_preprint":false},{"year":2008,"finding":"hMOF-mediated H4K16ac is specifically required for TMS1/ASC gene activity. Downregulation of hMOF or other MSL complex components causes gene-specific decrease in H4K16ac, loss of nucleosome positioning at TMS1, and silencing of TMS1 transcription. Gene silencing induced by H4K16 deacetylation occurs independently of changes in histone methylation and DNA methylation.","method":"ChIP, siRNA knockdown, bisulfite sequencing, gene expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, siRNA knockdown, multiple target loci; single lab","pmids":["18701507"],"is_preprint":false},{"year":2023,"finding":"MOF acetylates PRDX1 (peroxiredoxin 1) at lysine 197, preventing its hyperoxidation and maintaining its peroxidase activity under stress. PRDX1 K197ac decreases in mouse macrophages stimulated with LPS but not IL-4 or IL-10. Loss of K197ac elevates cellular hydrogen peroxide and augments ERK1/2 phosphorylation, stimulating glycolysis, H3S28 phosphorylation, and pro-inflammatory mediator (IL-6) production.","method":"In vitro acetylation assay, mass spectrometry, macrophage stimulation assays, Western blot, siRNA knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro acetylation assay, MS validation, functional stimulation assays; single lab with multiple orthogonal methods","pmids":["39207899"],"is_preprint":false},{"year":2024,"finding":"KAT8-mediated H4K16ac regulates CDX2 transcription and is essential for trophoblast stem cell self-renewal and proliferation. Trophoblast-specific Kat8 deletion leads to extraembryonic ectoderm abnormalities and embryonic lethality. CDX2 overexpression partially rescues Kat8 knockout defects. Reduced KAT8, CDX2, and H4K16ac are associated with recurrent pregnancy loss in clinical samples, and EX527 (SIRT1 inhibitor) treatment restores CDX2 levels and placental development.","method":"Conditional knockout, RNA-seq, CUT&Tag, CDX2 rescue experiments, pharmacological rescue with EX527, trophoblast organoids","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, CUT&Tag, genetic rescue, organoid model, clinical validation; multiple orthogonal methods","pmids":["38961108"],"is_preprint":false},{"year":2024,"finding":"KAT8 directly lactylates PCK2 (mitochondrial phosphoenolpyruvate carboxykinase 2) at Lys100, augmenting PCK2 kinase activity. PCK2-K100 lactylation competitively inhibits Parkin-mediated polyubiquitination of OXSM, leading to metabolic remodeling of mitochondrial fatty acid synthesis and exacerbating hepatic ferroptosis during ischemia/reperfusion injury.","method":"In vitro lactylation assay, gene-edited mice, Co-immunoprecipitation, ubiquitination assay","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro lactylation, Co-IP, gene-edited mice; single lab with multiple methods","pmids":["39853940"],"is_preprint":false},{"year":2024,"finding":"Mitochondria-localized MOF acetylates ATP5B at K201. Co-regulation of ATP5B K201 acetylation by MOF and SIRT3 impairs mitochondrial respiration and energy metabolism. Overexpression of mitochondria-targeted MOF in mice results in mitochondrial dysfunction, cardiac remodeling, and heart failure. SIRT3 knockout aggravates mtMOF-induced damage.","method":"Quantitative lysine acetylome analysis (mass spectrometry), conditional overexpression mouse model, SIRT3 knockout, in vitro respiration assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — acetylome MS, in vivo mouse models, in vitro functional assays; multiple methods in one study","pmids":["39392752"],"is_preprint":false},{"year":2023,"finding":"KAT8-mediated acetylation of YEATS4 at specific residues impairs YEATS4 interaction with HUWE1 (E3 ligase), preventing its ubiquitination and proteasomal degradation, thereby stabilizing YEATS4. KAT8 inhibitor MG149 decreases YEATS4 acetylation, reduces bladder cancer cell viability, and sensitizes cells to cisplatin.","method":"Co-immunoprecipitation, in vitro acetylation assay, ubiquitination assay, CRISPR-Cas9 screen, KAT8 inhibitor treatment","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro acetylation, ubiquitination assay; single lab with multiple methods","pmids":["38526153"],"is_preprint":false},{"year":2023,"finding":"KAT8 acetylates HSP90 at K754 as a lysine butyrylation (Kbu) writer, cooperating with HDAC11 as the eraser. SDCBP increases HSP90 K754 butyrylation and stability by competitively binding HDAC11. HSP90 Kbu contributes to 5-FU resistance in esophageal squamous cell carcinoma.","method":"Butyrylome profiling (mass spectrometry), co-immunoprecipitation, in vitro modification assay, gain/loss-of-function experiments","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry profiling, Co-IP, in vitro assay; single lab","pmids":["37460462"],"is_preprint":false},{"year":2024,"finding":"KAT8 triggers LTBP1 lactylation at lysine 752 (K752) via a KAT8-dependent mechanism in fibroblasts. Lactate (released from PLLA) is taken up via MCT1 and facilitates LTBP1 K752 lactylation, which increases collagen I and collagen III protein levels in fibroblasts.","method":"Lactylation assays, siRNA knockdown, Co-immunoprecipitation, Western blot","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/knockdown approach; limited reconstitution data in abstract","pmids":["39102921"],"is_preprint":false},{"year":2023,"finding":"MOF (KAT8) directly binds promoter regions of Runx2 and Osterix and physically interacts with these osteogenic transcription factors, promoting their transcription via H4K16ac. MOF inhibition (siRNA or MG149 inhibitor) reduces Runx2/Osterix expression and inhibits osteoblast differentiation.","method":"ChIP, Co-immunoprecipitation, siRNA knockdown, small molecule inhibitor (MG149)","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, siRNA; single lab with multiple methods","pmids":["37247031"],"is_preprint":false},{"year":2023,"finding":"hMOF acetylates MDM2, increasing MDM2 stability by inhibiting its ubiquitinated degradation. Increased MDM2 acetylation by hMOF reduces cisplatin-induced p53 accumulation and promotes cisplatin resistance in ovarian cancer cells. Genetic inhibition of MDM2 reverses hMOF-mediated cisplatin resistance.","method":"Co-immunoprecipitation, ubiquitination assay, Western blot, RNA-seq, siRNA knockdown, xenograft mouse model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft; single lab with multiple methods","pmids":["37291112"],"is_preprint":false},{"year":2017,"finding":"Glioma-induced activation of microglia involves SIRT1 nuclear localization leading to deacetylation of hMOF, which in turn results in hMOF chromatin recruitment at promoter regions of microglial target genes and increased H4K16ac in microglia, promoting a tumor-supporting phenotype.","method":"Subcellular fractionation, ChIP, siRNA knockdown, cell co-culture model","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, fractionation, siRNA; single lab with multiple methods","pmids":["29308302"],"is_preprint":false},{"year":2017,"finding":"Acetylation of hMOF modulates H4K16ac and DNA repair gene expression in response to oxidative stress. Hydrogen peroxide induces SIRT1, which decreases hMOF chromatin affinity and activity toward H4K16ac, resulting in decreased transcriptional expression of DNA repair genes independent of DNA methylation changes.","method":"RNA-seq, RRBS-seq, ChIP, siRNA knockdown","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq, ChIP, RRBS-seq; single lab with multiple methods","pmids":["28808424"],"is_preprint":false},{"year":2013,"finding":"KAT8 regulates G2/M cell cycle arrest through AKT/ERK-cyclin D1 signaling. KAT8 inhibition led to p53 induction and subsequently reduced Bcl-2 expression in lung cancer cells.","method":"RNAi screen, Western blot, flow cytometry, siRNA knockdown","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNAi screen with limited mechanistic follow-up; single lab, limited methods reported in abstract","pmids":["23638218"],"is_preprint":false},{"year":2014,"finding":"hMOF regulates the expression of SIRT6 and its downstream genes in hepatocellular carcinoma cells. hMOF knockdown promotes HCC growth while overexpression reduces it, and the effect is mechanistically linked to SIRT6 regulation.","method":"siRNA knockdown, overexpression, ChIP (implied), in vitro and in vivo tumor growth assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown/overexpression with mechanistic link to SIRT6, but limited biochemical detail in abstract","pmids":["25181338"],"is_preprint":false},{"year":2015,"finding":"MOF directly binds and maintains expression of cell cycle progression genes in proliferating cells (via NSL complex) but is dispensable for terminally differentiated podocytes under physiological conditions. Under injury stress, MOF is critical for podocyte maintenance, with genome-wide analysis revealing MOF directly binds lysosome, endocytosis, and vacuole pathway genes.","method":"Conditional knockout, ChIP-seq, RNA-seq, genome-wide expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout, ChIP-seq, RNA-seq; single lab, multiple methods","pmids":["26387537"],"is_preprint":false}],"current_model":"KAT8 (hMOF/MYST1) is a MYST-family lysine acetyltransferase that, as part of the MSL complex, catalyzes the bulk of H4K16 acetylation via a ping-pong kinetic mechanism (Ac-CoA binding first, dependent on K274 autoacetylation for stability and activity), and as part of the NSL complex catalyzes H4K5ac and H4K8ac to support housekeeping gene transcription; beyond histones, KAT8 acetylates numerous non-histone substrates including IRF3 (suppressing antiviral immunity), Nrf2 (promoting nuclear retention), LSD1 (inhibiting EMT), DBC1 (regulating SirT1 activity), PRDX1 (controlling macrophage redox signaling), COX17 (supporting mitochondrial complex IV), and ATP5B (regulating mitochondrial energy metabolism), and additionally acts as a lactyltransferase/butyrylation writer for targets including eEF1A2 and HSP90; KAT8 activity is regulated by SIRT1-mediated deacetylation (inhibiting activity and promoting degradation), USP10-mediated deubiquitination (stabilizing the protein), and autoacetylation at K274, while its subcellular distribution spans both the nucleus and mitochondria, the latter pool being dependent on KANSL3 and required for oxidative phosphorylation and mtDNA transcription."},"narrative":{"mechanistic_narrative":"KAT8 (hMOF/MYST1) is a MYST-family lysine acetyltransferase that controls chromatin state and gene expression principally through histone H4 acetylation, and additionally acts on a broad set of non-histone substrates to regulate genome stability, redox balance, immunity, and mitochondrial function [PMID:16024812, PMID:33657400]. It catalyzes the bulk of cellular H4K16 acetylation as part of the MSL complex (with partners including hMSL3), while in the NSL complex it deposits H4K5ac and H4K8ac to drive transcription initiation at housekeeping gene promoters; depletion experiments show the NSL function is essential for cell survival whereas MSL/H4K16ac is dispensable for proliferation and chromatin accessibility [PMID:16024812, PMID:33657400]. Its catalytic mechanism is ping-pong, with acetyl-CoA binding first followed by substrate, and depends on autoacetylation of the MYST domain at K274, which stabilizes the enzyme and is required for activity—any substitution at K274 disorders the active-site loop and abolishes function [PMID:26505788, PMID:27382063, PMID:21502975]. KAT8 is genetically essential in vivo: its loss blocks embryonic development past the blastocyst stage with specific failure of H4K16ac and induction of apoptosis [PMID:18541669], and tissue-specific deletion impairs oocyte and trophoblast development, the latter via H4K16ac-dependent control of CDX2 [PMID:28506985, PMID:38961108]. Through H4K16ac it couples chromatin to the DNA-damage response, interacting with ATM and supporting ATM activation and repair after ionizing radiation [PMID:15923642, PMID:16024812], and regulates RNA Pol II pause release via BRD4/pTEFb recruitment [PMID:21321083]. KAT8 also extends acetylation to non-histone targets to tune diverse pathways: it acetylates IRF3 to suppress type-I interferon responses [PMID:30842237], Nrf2 to promote its nuclear retention and antioxidant gene expression [PMID:24571482], LSD1 to restrain EMT [PMID:27292636], and DBC1 to modulate SirT1 activity [PMID:24126058]. A distinct mitochondrial pool, dependent on the NSL component KANSL3, binds mtDNA and is required for oxidative phosphorylation and respiratory gene transcription, with catalytic activity necessary for rescue [PMID:27768893]; in mitochondria KAT8 acetylates the complex IV assembly factor COX17 and ATP5B to govern respiration and energy metabolism [PMID:37813994, PMID:39392752]. KAT8 itself is regulated by SIRT1-mediated deacetylation of its MYST domain, which inhibits activity and promotes ubiquitin-dependent degradation, and by USP10-mediated deubiquitination that stabilizes the protein [PMID:21502975, PMID:22586264, PMID:38317006]. Beyond classical acetylation, KAT8 also functions as a lactyltransferase and butyrylation writer for substrates including eEF1A2 and HSP90 [PMID:38359291, PMID:37460462]. KAT8 contributes to malignancy, supporting MLL-AF9-driven leukemogenesis in a catalytic-activity-dependent manner [PMID:28202522].","teleology":[{"year":2005,"claim":"Established KAT8 as the enzyme responsible for the bulk of mammalian H4K16 acetylation and linked it physically and functionally to the DNA-damage response.","evidence":"siRNA knockdown with mass spectrometry of endogenous histones, Co-IP with hMSL3 and ATM, kinase and DNA repair assays in human cells","pmids":["16024812","15923642"],"confidence":"High","gaps":["Did not resolve which complex (MSL vs NSL) drives the repair phenotype","Mechanism of ATM activation by H4K16ac left structural"]},{"year":2008,"claim":"Demonstrated that KAT8 is non-redundantly required for development and that its function is specific to H4K16, not other histone lysines.","evidence":"Mof-null/conditional knockout mouse embryos with immunofluorescence, Western blot, and caspase-3 assays; gene-specific TMS1 ChIP studies","pmids":["18541669","18701507"],"confidence":"High","gaps":["Did not separate chromatin vs non-histone roles in lethality","Downstream gene programs underlying apoptosis not fully mapped"]},{"year":2011,"claim":"Defined autoacetylation at K274 in the MYST domain as a regulatory switch and SIRT1 as its eraser controlling chromatin recruitment.","evidence":"In vitro acetylation and nucleosome-binding assays, Co-IP, and ChIP","pmids":["21502975","21321083"],"confidence":"High","gaps":["Whether autoacetylation is intramolecular or intermolecular not settled","Quantitative contribution of autoacetylation vs SIRT1 in vivo unclear"]},{"year":2012,"claim":"Showed SIRT1 deacetylation of the MYST domain inhibits KAT8 activity and triggers its degradation, coupling enzyme turnover to DNA damage.","evidence":"In vitro deacetylation, mutagenesis of target lysines, ubiquitination and DSB repair assays","pmids":["22586264"],"confidence":"High","gaps":["E3 ligase mediating degradation not identified","Kinetics of transient SIRT1 dissociation after damage not quantified"]},{"year":2013,"claim":"Connected KAT8/H4K16ac to autophagy outcome and to non-histone control of SirT1 activity via DBC1 acetylation.","evidence":"Genome-wide ChIP-seq, siRNA knockdown, viability assays; in vitro DBC1 acetylation with mutagenesis","pmids":["23863932","24126058"],"confidence":"High","gaps":["Signal triggering KAT8 downregulation during autophagy not fully defined","Interplay between chromatin and DBC1 routes not integrated"]},{"year":2015,"claim":"Resolved the enzymatic mechanism as ordered ping-pong with acetyl-CoA binding first, providing a kinetic framework and inhibitor basis.","evidence":"Enzyme kinetics and isothermal titration calorimetry with anacardic acid inhibitor analysis","pmids":["26505788"],"confidence":"High","gaps":["Done with isolated enzyme, not in complex context","Substrate selectivity within MSL vs NSL not addressed kinetically"]},{"year":2016,"claim":"Established a catalytically required mitochondrial pool of KAT8 controlling oxidative phosphorylation and mtDNA transcription, and structurally explained K274 dependence.","evidence":"Subcellular fractionation, ChIP on mtDNA, cardiac conditional knockout, catalytic-mutant rescue; X-ray crystallography of K274P mutant","pmids":["27768893","27382063","27292636","24571482"],"confidence":"High","gaps":["Mechanism of KAT8 mitochondrial import not defined","Mitochondrial substrates incompletely catalogued at this stage"]},{"year":2019,"claim":"Extended KAT8 function to innate immunity by showing direct IRF3 acetylation suppresses type-I interferon responses.","evidence":"Co-IP, in vitro acetylation, ChIP, and mouse viral challenge","pmids":["30842237"],"confidence":"High","gaps":["Whether nuclear vs cytoplasmic KAT8 acts on IRF3 unclear","Complex dependence of IRF3 acetylation not defined"]},{"year":2021,"claim":"Separated KAT8 functions by complex: NSL-driven H4K5/K8ac is essential for housekeeping transcription whereas MSL-driven H4K16ac is dispensable for proliferation.","evidence":"Auxin-inducible degron depletion with mass spectrometry, ATAC-seq, RNA-seq, ChIP-seq; fibrosis ChIP/rescue work","pmids":["33657400","34285225"],"confidence":"High","gaps":["How complex partitioning is regulated in cells not resolved","Reconciliation with earlier H4K16ac-essential phenotypes incomplete"]},{"year":2023,"claim":"Broadened the substrate and modification repertoire to mitochondrial COX17 acetylation and to condensate-based IRF1 acetylation controlling PD-L1, plus butyrylation of HSP90.","evidence":"In vitro acetylation, Co-IP, electron microscopy and acetyl-mimetic rescue; phase-separation assays with blocking peptide and tumor models; butyrylome profiling","pmids":["37813994","36894639","37460462","39207899"],"confidence":"High","gaps":["Determinants of substrate vs modification choice (acetyl/butyryl) unknown","Physiological triggers for condensate formation incompletely defined"]},{"year":2024,"claim":"Identified KAT8 as a lactyltransferase writer acting on eEF1A2, PCK2, and other targets, and confirmed USP10-mediated stabilization controlling its oncogenic output.","evidence":"Lactylome profiling, in vitro lactylation, Co-IP, ubiquitination assays, and KAT8 deletion/gene-edited mouse models","pmids":["38359291","39853940","38317006","39392752"],"confidence":"High","gaps":["Active-site basis for lactyl vs acetyl transfer not structurally defined","How metabolic lactate levels gate KAT8 writer activity unresolved"]},{"year":null,"claim":"How a single MYST enzyme selects among acyl-CoA donors (acetyl, lactyl, butyryl), histone vs non-histone substrates, and nuclear vs mitochondrial compartments remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model distinguishing donor selectivity","Regulation of compartmental partitioning between nucleus and mitochondria undefined","Rules governing complex assembly (MSL vs NSL) in different cell types unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,10,12,13,14,18,33]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8,9,19,35]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,21,37]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,7,15]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,18,33]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,12,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,6,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[10,12,13,18,35]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,18,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11]}],"complexes":["MSL complex","NSL complex"],"partners":["MSL3","ATM","SIRT1","KANSL3","IRF3","USP10","NRF2","LSD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H7Z6","full_name":"Histone acetyltransferase KAT8","aliases":["Lysine acetyltransferase 8","MOZ, YBF2/SAS3, SAS2 and TIP60 protein 1","MYST-1","Males-absent on the first protein homolog","hMOF","Protein acetyltransferase KAT8","Protein propionyltransferase KAT8"],"length_aa":458,"mass_kda":52.4,"function":"Histone acetyltransferase that catalyzes histone H4 acetylation at 'Lys-5'- and 'Lys-8' (H4K5ac and H4K8ac) or 'Lys-16' (H4K16ac), depending on the context (PubMed:12397079, PubMed:16227571, PubMed:16543150, PubMed:20018852, PubMed:21217699, PubMed:22020126, PubMed:22547026, PubMed:31794431, PubMed:33837287). Catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at 'Lys-16' (H4K16ac), an epigenetic mark that prevents chromatin compaction (PubMed:12397079, PubMed:16227571, PubMed:16543150, PubMed:21217699, PubMed:22020126, PubMed:22547026, PubMed:33657400, PubMed:33837287). H4K16ac constitutes the only acetylation mark intergenerationally transmitted and regulates key biological processes, such as oogenesis, embryonic stem cell pluripotency, hematopoiesis or glucose metabolism (By similarity). The MSL complex is required for chromosome stability and genome integrity by maintaining homeostatic levels of H4K16ac (PubMed:33837287). The MSL complex is also involved in gene dosage by promoting up-regulation of genes expressed by the X chromosome (By similarity). X up-regulation is required to compensate for autosomal biallelic expression (By similarity). The MSL complex also participates in gene dosage compensation by promoting expression of Tsix non-coding RNA (By similarity). As part of the NSL histone acetyltransferase complex, catalyzes histone H4 acetylation at 'Lys-5'- and 'Lys-8' (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiation (PubMed:20018852, PubMed:22547026, PubMed:33657400). The NSL complex also acts as a regulator of gene expression in mitochondria: KAT8 associates with mitochondrial DNA and controls expression of respiratory genes in an acetyltransferase-dependent mechanism (PubMed:27768893). Also functions as an acetyltransferase for non-histone targets, such as ALKBH5, COX17, IRF3, KDM1A/LSD1, LMNA, PAX7 or TP53/p53 (PubMed:17189187, PubMed:19854137, PubMed:37369679). Acts as an inhibitor of antiviral immunity by acetylating IRF3, preventing IRF3 recruitment to promoters (By similarity). Acts as a regulator of asymmetric division in muscle stem cells by mediating acetylation of PAX7 (By similarity). As part of the NSL complex, acetylates TP53/p53 at 'Lys-120' (PubMed:17189187, PubMed:19854137). Acts as a regulator of epithelial-to-mesenchymal transition as part of the NSL complex by mediating acetylation of KDM1A/LSD1 (PubMed:27292636). The NSL complex is required for nuclear architecture maintenance by mediating acetylation of LMNA (By similarity). Promotes mitochondrial integrity by catalyzing acetylation of COX17 (By similarity). In addition to protein acetyltransferase activity, able to mediate protein propionylation (PubMed:29321206)","subcellular_location":"Nucleus; Chromosome; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9H7Z6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT8","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PBK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KAT8","total_profiled":1310},"omim":[{"mim_id":"618974","title":"LI-GHORBANI-WEISZ-HUBSHMAN SYNDROME; LIGOWS","url":"https://www.omim.org/entry/618974"},{"mim_id":"617742","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 3; KANSL3","url":"https://www.omim.org/entry/617742"},{"mim_id":"616856","title":"BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN 3; BRPF3","url":"https://www.omim.org/entry/616856"},{"mim_id":"615488","title":"KAT8 REGULATORY NSL COMPLEX, SUBUNIT 2; KANSL2","url":"https://www.omim.org/entry/615488"},{"mim_id":"613833","title":"KAT8 REGULATORY NSL COMPLEX SUBUNIT 1-LIKE PROTEIN; KANSL1L","url":"https://www.omim.org/entry/613833"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KAT8"},"hgnc":{"alias_symbol":["MOF","FLJ14040","hMOF"],"prev_symbol":["MYST1"]},"alphafold":{"accession":"Q9H7Z6","domains":[{"cath_id":"2.30.30.140","chopping":"52-121","consensus_level":"medium","plddt":86.041,"start":52,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7Z6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7Z6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H7Z6-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KAT8","jax_strain_url":"https://www.jax.org/strain/search?query=KAT8"},"sequence":{"accession":"Q9H7Z6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H7Z6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H7Z6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H7Z6"}},"corpus_meta":[{"pmid":"28451673","id":"PMC_28451673","title":"Enzyme-MOF 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Knockdown of hMOF in HeLa and HepG2 cells causes dramatic reduction of H4K16ac (confirmed by Western blot and mass spectrometry). hMOF and hMSL3 form a complex in mammalian cells. hMOF-depleted cells accumulate in G2/M and show impaired DNA damage repair response to ionizing radiation, with increased phospho-ATM and γH2AX foci.\",\n      \"method\": \"siRNA knockdown, Western blot, mass spectrometric analysis of endogenous histones, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, mass spectrometry validation, multiple orthogonal methods, independently replicated across multiple labs\",\n      \"pmids\": [\"16024812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"hMOF interacts with ATM protein, and hMOF-dependent H4K16ac is required for ATM autophosphorylation, ATM kinase activity, and downstream effector phosphorylation after ionizing radiation. Blocking H4K16ac increase (via dominant-negative hMOF or siRNA) decreases ATM function and DNA repair while increasing cell killing.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutant expression, siRNA knockdown, kinase assays, immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, dominant-negative and RNAi approaches, replicated with multiple methods in one study\",\n      \"pmids\": [\"15923642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mof (KAT8) is essential for embryonic development past the blastocyst stage in mice. Mof-null embryos fail to acetylate H4K16 but have normal acetylation of other histone lysine residues, demonstrating non-redundant and specific function. Loss of Mof causes abnormal chromatin aggregation preceding caspase-3 activation and DNA fragmentation.\",\n      \"method\": \"Conditional knockout mouse model, immunofluorescence, Western blot, caspase-3 assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific phenotypic readout, multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"18541669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Autophagy induction leads to downregulation of hMOF, causing reduction of H4K16ac, which is associated predominantly with downregulation of autophagy-related genes. Antagonizing H4K16ac downregulation during autophagy induction promotes cell death, establishing a feedback loop where H4K16ac levels determine the survival vs. death outcome of autophagy.\",\n      \"method\": \"Western blot, genome-wide ChIP-seq, siRNA knockdown, cell viability assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, multiple orthogonal methods, published in Nature with rigorous controls\",\n      \"pmids\": [\"23863932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KAT8/MOF and a subset of its NSL complex partners reside in mitochondria in addition to the nucleus. Mitochondrial MOF binds mtDNA (dependent on KANSL3) and regulates oxidative phosphorylation by controlling expression of respiratory genes from both nuclear and mtDNA. A catalytically deficient MOF mutant fails to rescue respiratory and mtDNA transcriptional defects, indicating catalytic activity is required.\",\n      \"method\": \"Subcellular fractionation, ChIP, conditional knockout mouse model (cardiac), RNA-seq, catalytic mutant rescue experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fractionation, ChIP, catalytic mutant rescue, in vivo knockout with defined phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"27768893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAT8 exhibits complex-dependent catalytic activity: as part of the NSL complex it catalyzes H4K5ac and H4K8ac, whereas as part of the MSL complex it catalyzes the bulk of H4K16ac. MSL complex proteins and H4K16ac are not required for cell proliferation and chromatin accessibility, whereas the NSL complex is essential for cell survival by stimulating transcription initiation at housekeeping gene promoters.\",\n      \"method\": \"Auxin-inducible degron system for protein depletion, mass spectrometry, ATAC-seq, RNA-seq, ChIP-seq\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical fractionation, mass spectrometry, multiple genome-wide assays, rigorous controls with depletion system\",\n      \"pmids\": [\"33657400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SIRT1 deacetylates the enzymatic (MYST) domains of hMOF and TIP60, inhibiting their acetyltransferase activity and promoting ubiquitination-dependent degradation. Immediately following DNA damage, SIRT1 binding to hMOF is transiently interrupted with corresponding hMOF hyperacetylation. Lysine-to-arginine mutations at SIRT1-targeted lysines on hMOF repress DNA double-strand break repair and inhibit apoptosis induction.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylation assay, mutagenesis, ubiquitination assay, DNA damage repair assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro assay, mutagenesis, reciprocal Co-IP, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22586264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hMOF undergoes autoacetylation in vitro and in vivo, restricted to the MYST domain with K274 as the major autoacetylation site. SIRT1 interacts with the MYST domain of hMOF and deacetylates it. Non-acetylated hMOF binds nucleosomes more robustly; acetylation decreases nucleosome binding. SIRT1 deacetylation of hMOF promotes its chromatin recruitment and H4K16ac activity.\",\n      \"method\": \"In vitro acetylation assay, co-immunoprecipitation, in vitro nucleosome binding assay, ChIP, siRNA knockdown\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, nucleosome binding assay, ChIP; multiple methods in one study\",\n      \"pmids\": [\"21502975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Structural and mutational analysis of hMOF K274 autoacetylation reveals that all amino acid substitutions at K274 result in significant destabilization of hMOF and complete loss of catalytic activity toward histone H4. X-ray crystal structure of K274P mutant shows disordering of the α2-β7 loop harboring K274, explaining loss of function. K274 autoacetylation (driven by Ac-CoA binding) is required for hMOF stability and cognate substrate acetylation.\",\n      \"method\": \"X-ray crystallography, mutagenesis, in vitro acetyltransferase assay, stability measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro assay, multiple orthogonal methods\",\n      \"pmids\": [\"27382063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KAT8 follows a ping-pong kinetic mechanism in which Ac-CoA binds first, followed by the histone substrate. This was confirmed by isothermal titration calorimetry (ITC) affinity measurements of both substrates. Anacardic acid inhibits KAT8 via this mechanism and the inhibition constants of anacardic acid derivatives were calculated.\",\n      \"method\": \"Enzyme kinetics, isothermal titration calorimetry (ITC), inhibitor assays\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic mechanism established by kinetics and ITC, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26505788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT8 directly interacts with IRF3 via its MYST domain and mediates IRF3 acetylation at lysine 359, inhibiting IRF3 recruitment to IFN-I gene promoters and decreasing its transcriptional activity. KAT8 deficiency in mice protects from viral challenge by enhancing IFN-I production.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, ChIP, siRNA screen, mouse viral challenge model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro acetylation assay, Co-IP, ChIP, in vivo mouse model; multiple orthogonal methods\",\n      \"pmids\": [\"30842237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In response to IFNγ, KAT8 undergoes phase separation with IRF1 and forms biomolecular condensates, which promotes IRF1 K78 acetylation and its binding to the PD-L1 (CD274) promoter, enriching transcription apparatus and upregulating PD-L1 mRNA. Multivalency from specific and promiscuous IRF1-KAT8 interactions is required for condensate formation. A blocking peptide (2142-R8) that disrupts KAT8-IRF1 condensate formation inhibits PD-L1 expression and enhances antitumor immunity.\",\n      \"method\": \"Phase separation assays, Co-immunoprecipitation, in vitro acetylation assay, ChIP, blocking peptide experiments, in vivo tumor models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, in vitro assay, ChIP, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"36894639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hMOF physically interacts with Nrf2 and acetylates it at Lys588. MOF-mediated acetylation increases nuclear retention of Nrf2 and transcription of its downstream genes. MOF/hMOF is essential for anti-oxidative and anti-drug responses in an Nrf2-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, nuclear fractionation, siRNA knockdown, reporter assay, mouse xenograft\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, fractionation, in vivo validation; multiple methods in one study\",\n      \"pmids\": [\"24571482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"hMOF (KAT8) is responsible for acetylation of DBC1/CCAR2 at K112 and K215. Acetylation of these residues inhibits DBC1-SirT1 binding and increases SirT1 deacetylase activity. After DNA damage, ATM-dependent inhibition of hMOF binding to DBC1 leads to DBC1 deacetylation and increased SirT1-DBC1 binding. A DBC1 acetylation-mimic mutant fails to promote apoptosis after DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, DNA damage assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, mutagenesis; multiple methods in one study\",\n      \"pmids\": [\"24126058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MOF acetyltransferase interacts with LSD1 and is responsible for acetylation of LSD1 in epithelial cells. Acetylation of LSD1 reduces its association with nucleosomes, increasing H3K4 methylation at LSD1 target genes and activating transcription. MOF expression is downregulated by EMT-inducing signals, and MOF depletion enhances EMT and tumor metastasis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, nucleosome association assay, ChIP, siRNA knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro acetylation assay, Co-IP, ChIP; multiple orthogonal methods\",\n      \"pmids\": [\"27292636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUV420H2-mediated H4K20me3 and hMOF-mediated H4K16ac play opposing roles in RNA Pol II promoter-proximal pausing. H4K16ac promotes release of Pol II from pausing through recruitment of BRD4 and pTEFb. H4K20me3 blocks Pol II escape by locally inhibiting H4K16ac. Combined inhibition of H4K20me3 and DNA methylation results in re-recruitment of hMOF, H4K16ac, and synergistic reactivation of gene expression.\",\n      \"method\": \"ChIP, siRNA knockdown, inhibitor treatments, reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP experiments, siRNA knockdown, multiple gene targets tested\",\n      \"pmids\": [\"21321083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MOF (MSL complex) specifically regulates Tsix, the major repressor of Xist lncRNA, in mouse embryonic stem cells. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently enhanced Xist accumulation and variable X-chromosome inactivation during differentiation. The NSL complex provides additional Tsix-independent repression of Xist by maintaining pluripotency.\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA knockdown, allele-specific analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, RNA-seq, genetic depletion with specific phenotypic readout\",\n      \"pmids\": [\"24842875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGFβ activates autophagy via SMAD3-dependent downregulation of MYST1 (KAT8), which regulates expression of core autophagy components ATG7 and BECLIN1 via H4K16 acetylation. Autophagy activation in fibroblasts promotes collagen release and is required to induce tissue fibrosis. Forced expression of MYST1 abrogates TGFβ-stimulated autophagy.\",\n      \"method\": \"ChIP, siRNA knockdown, overexpression, mouse fibrosis models, Western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, genetic rescue, in vivo mouse models; multiple orthogonal methods, replicated across fibrosis models\",\n      \"pmids\": [\"34285225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOF (via its KANSL complex) acetylates COX17, a complex IV assembly factor, at a specific residue. Loss of MOF-KANSL complex leads to mitochondrial fragmentation, reduced cristae density, and impaired electron transport chain complex IV integrity. Expression of acetylation-mimetic COX17 rescues these defects even in the absence of MOF, demonstrating that COX17 acetylation is a critical downstream effector of MOF in mitochondrial physiology.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mitochondrial fractionation, electron microscopy, acetylation-mimetic mutant rescue experiments, patient fibroblasts\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro acetylation, Co-IP, structural imaging, acetylation mimic rescue; multiple orthogonal methods, patient-derived validation\",\n      \"pmids\": [\"37813994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8 acts as a pan-lactyltransferase (Kla writer) capable of installing lysine lactylation on multiple protein substrates. KAT8 specifically lactylates eEF1A2 at K408, boosting translation elongation and protein synthesis contributing to colorectal cancer tumorigenesis. Deletion of KAT8 inhibited CRC tumor growth, especially in high-lactic tumor microenvironments.\",\n      \"method\": \"Proteomics/lactylome profiling, co-immunoprecipitation, in vitro lactylation assay, KAT8 deletion mouse models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro lactylation assay, proteomics, Co-IP, in vivo genetic deletion; multiple orthogonal methods\",\n      \"pmids\": [\"38359291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MOF HAT activity is required for MLL-AF9-driven leukemogenesis. Conditional deletion of Mof in MLL-AF9 mouse leukemia model reduced tumor burden and prolonged survival. Rescue experiments with catalytically inactive MOF mutants showed enzymatic activity is required for cancer pathogenicity. MOF loss impaired global H4K16ac and increased γH2AX foci.\",\n      \"method\": \"Conditional knockout mouse model, catalytic mutant rescue experiments, RNA-seq, immunofluorescence\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model, catalytic mutant rescue, multiple cancer models tested\",\n      \"pmids\": [\"28202522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KAT8 is essential for mouse oocyte development. Oocyte-specific deletion of Kat8 causes female infertility with follicle development failure. KAT8 deficiency results in significant downregulation of antioxidant genes with consequent ROS increase, which can be rescued by N-acetylcysteine. ChIP assays show KAT8 directly binds promoter regions of antioxidant genes.\",\n      \"method\": \"Conditional knockout (Gdf9-Cre), RNA-seq, ChIP, antioxidant rescue experiments (N-acetylcysteine injection)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional knockout, ChIP, pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"28506985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MOF regulates erythropoiesis by dynamic chromatin recruitment; its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator necessary and sufficient for cell-type-specific induction of Mof expression. Mof-depleted HSC plasticity can be rescued by downstream effector GATA1 or HDAC inhibitor-mediated rebalancing of acetylation.\",\n      \"method\": \"Single-cell RNA-seq, ChIP-seq, genetic rescue experiments, HDAC inhibitor treatment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq, ChIP-seq, genetic rescue; multiple methods in one study\",\n      \"pmids\": [\"32671208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYST1 (KAT8) co-stimulates androgen receptor (AR) and NF-κB functions in prostate cancer cells. NF-κB activation promotes SIRT1-mediated deacetylation of MYST1, and mutually exclusive interactions of MYST1 with SIRT1 vs. AR regulate H4K16ac. MYST1 depletion in AR-lacking cells triggers PARP/caspase-3 cleavage (apoptosis), while in AR-transformed cells it induces CDK N1A/p21 and G2M arrest.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ChIP, cell cycle analysis, Western blot\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ChIP, knockdown; single lab with multiple methods but limited reconstitution\",\n      \"pmids\": [\"24702180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KAT8 colocalizes with WDR5 at androgen receptor (AR) target genes. PKN1/H3T11 phosphorylation leads to WDR5/MLL methyltransferase recruitment, which then recruits KAT8 to effect H4K16ac and AR-dependent gene activation. KAT8 knockdown significantly decreased AR target gene expression and prostate cancer cell proliferation.\",\n      \"method\": \"ChIP, siRNA knockdown, Co-immunoprecipitation, gene expression analysis\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, and knockdown; single lab, multiple methods\",\n      \"pmids\": [\"27268279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TET1 forms a chromatin complex with hMOF and Sin3a in mouse embryonic stem cells. TET1 facilitates chromatin affinity and enzymatic activity of hMOF toward H4K16ac by preventing hMOF autoacetylation, thereby regulating expression of downstream genes including DNA repair genes. Tet1 knockout cells show DNA damage accumulation and genomic instability.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq analysis (integrative genomics), in vitro biochemical studies, Tet1 knockout MEF cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro biochemistry, ChIP-seq integration; single lab with multiple methods\",\n      \"pmids\": [\"27733505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MOF interacts with PCNA at replication forks and affects PCNA ubiquitination and recruitment to DNA damage sites. MOF depletion in cells under replicative stress decreases replication fork speed, increases stalled replication forks, promotes new origin firing, and increases R-loop formation. MOF depletion also compromises DNA end resection and CHK1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, DNA fiber assay, PCNA ubiquitination assay, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, DNA fiber assay, ubiquitination assay; single lab with multiple methods\",\n      \"pmids\": [\"29298824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WSTF lysine 426 is acetylated by MOF (via MSL1v1-mediated interaction) and deacetylated by SIRT1. WSTF K426 acetylation promotes WSTF Ser158 phosphorylation, enhancing WSTF kinase and transcriptional regulatory activity and cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, cell proliferation and invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro acetylation assay, Co-IP, mutagenesis; single lab\",\n      \"pmids\": [\"32518374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP10 (a deubiquitinase) binds to and deubiquitinates MOF at lysine 410, protecting it from proteasome-dependent degradation. MOF stabilization by USP10 promotes H4K16ac enrichment at the ANXA2 promoter (in a JUN-dependent manner), stimulating ANXA2 transcription and activating Wnt/β-Catenin signaling to facilitate esophageal cancer progression. Catalytically inactive MOF-E350Q fails to promote progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, catalytic mutant rescue, siRNA knockdown, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP, catalytic mutant; multiple orthogonal methods in one study\",\n      \"pmids\": [\"38317006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hMOF-mediated H4K16ac is specifically required for TMS1/ASC gene activity. Downregulation of hMOF or other MSL complex components causes gene-specific decrease in H4K16ac, loss of nucleosome positioning at TMS1, and silencing of TMS1 transcription. Gene silencing induced by H4K16 deacetylation occurs independently of changes in histone methylation and DNA methylation.\",\n      \"method\": \"ChIP, siRNA knockdown, bisulfite sequencing, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, siRNA knockdown, multiple target loci; single lab\",\n      \"pmids\": [\"18701507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOF acetylates PRDX1 (peroxiredoxin 1) at lysine 197, preventing its hyperoxidation and maintaining its peroxidase activity under stress. PRDX1 K197ac decreases in mouse macrophages stimulated with LPS but not IL-4 or IL-10. Loss of K197ac elevates cellular hydrogen peroxide and augments ERK1/2 phosphorylation, stimulating glycolysis, H3S28 phosphorylation, and pro-inflammatory mediator (IL-6) production.\",\n      \"method\": \"In vitro acetylation assay, mass spectrometry, macrophage stimulation assays, Western blot, siRNA knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro acetylation assay, MS validation, functional stimulation assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39207899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8-mediated H4K16ac regulates CDX2 transcription and is essential for trophoblast stem cell self-renewal and proliferation. Trophoblast-specific Kat8 deletion leads to extraembryonic ectoderm abnormalities and embryonic lethality. CDX2 overexpression partially rescues Kat8 knockout defects. Reduced KAT8, CDX2, and H4K16ac are associated with recurrent pregnancy loss in clinical samples, and EX527 (SIRT1 inhibitor) treatment restores CDX2 levels and placental development.\",\n      \"method\": \"Conditional knockout, RNA-seq, CUT&Tag, CDX2 rescue experiments, pharmacological rescue with EX527, trophoblast organoids\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, CUT&Tag, genetic rescue, organoid model, clinical validation; multiple orthogonal methods\",\n      \"pmids\": [\"38961108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8 directly lactylates PCK2 (mitochondrial phosphoenolpyruvate carboxykinase 2) at Lys100, augmenting PCK2 kinase activity. PCK2-K100 lactylation competitively inhibits Parkin-mediated polyubiquitination of OXSM, leading to metabolic remodeling of mitochondrial fatty acid synthesis and exacerbating hepatic ferroptosis during ischemia/reperfusion injury.\",\n      \"method\": \"In vitro lactylation assay, gene-edited mice, Co-immunoprecipitation, ubiquitination assay\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro lactylation, Co-IP, gene-edited mice; single lab with multiple methods\",\n      \"pmids\": [\"39853940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mitochondria-localized MOF acetylates ATP5B at K201. Co-regulation of ATP5B K201 acetylation by MOF and SIRT3 impairs mitochondrial respiration and energy metabolism. Overexpression of mitochondria-targeted MOF in mice results in mitochondrial dysfunction, cardiac remodeling, and heart failure. SIRT3 knockout aggravates mtMOF-induced damage.\",\n      \"method\": \"Quantitative lysine acetylome analysis (mass spectrometry), conditional overexpression mouse model, SIRT3 knockout, in vitro respiration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — acetylome MS, in vivo mouse models, in vitro functional assays; multiple methods in one study\",\n      \"pmids\": [\"39392752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT8-mediated acetylation of YEATS4 at specific residues impairs YEATS4 interaction with HUWE1 (E3 ligase), preventing its ubiquitination and proteasomal degradation, thereby stabilizing YEATS4. KAT8 inhibitor MG149 decreases YEATS4 acetylation, reduces bladder cancer cell viability, and sensitizes cells to cisplatin.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, ubiquitination assay, CRISPR-Cas9 screen, KAT8 inhibitor treatment\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro acetylation, ubiquitination assay; single lab with multiple methods\",\n      \"pmids\": [\"38526153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT8 acetylates HSP90 at K754 as a lysine butyrylation (Kbu) writer, cooperating with HDAC11 as the eraser. SDCBP increases HSP90 K754 butyrylation and stability by competitively binding HDAC11. HSP90 Kbu contributes to 5-FU resistance in esophageal squamous cell carcinoma.\",\n      \"method\": \"Butyrylome profiling (mass spectrometry), co-immunoprecipitation, in vitro modification assay, gain/loss-of-function experiments\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry profiling, Co-IP, in vitro assay; single lab\",\n      \"pmids\": [\"37460462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT8 triggers LTBP1 lactylation at lysine 752 (K752) via a KAT8-dependent mechanism in fibroblasts. Lactate (released from PLLA) is taken up via MCT1 and facilitates LTBP1 K752 lactylation, which increases collagen I and collagen III protein levels in fibroblasts.\",\n      \"method\": \"Lactylation assays, siRNA knockdown, Co-immunoprecipitation, Western blot\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/knockdown approach; limited reconstitution data in abstract\",\n      \"pmids\": [\"39102921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MOF (KAT8) directly binds promoter regions of Runx2 and Osterix and physically interacts with these osteogenic transcription factors, promoting their transcription via H4K16ac. MOF inhibition (siRNA or MG149 inhibitor) reduces Runx2/Osterix expression and inhibits osteoblast differentiation.\",\n      \"method\": \"ChIP, Co-immunoprecipitation, siRNA knockdown, small molecule inhibitor (MG149)\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, siRNA; single lab with multiple methods\",\n      \"pmids\": [\"37247031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"hMOF acetylates MDM2, increasing MDM2 stability by inhibiting its ubiquitinated degradation. Increased MDM2 acetylation by hMOF reduces cisplatin-induced p53 accumulation and promotes cisplatin resistance in ovarian cancer cells. Genetic inhibition of MDM2 reverses hMOF-mediated cisplatin resistance.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, Western blot, RNA-seq, siRNA knockdown, xenograft mouse model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo xenograft; single lab with multiple methods\",\n      \"pmids\": [\"37291112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Glioma-induced activation of microglia involves SIRT1 nuclear localization leading to deacetylation of hMOF, which in turn results in hMOF chromatin recruitment at promoter regions of microglial target genes and increased H4K16ac in microglia, promoting a tumor-supporting phenotype.\",\n      \"method\": \"Subcellular fractionation, ChIP, siRNA knockdown, cell co-culture model\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, fractionation, siRNA; single lab with multiple methods\",\n      \"pmids\": [\"29308302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Acetylation of hMOF modulates H4K16ac and DNA repair gene expression in response to oxidative stress. Hydrogen peroxide induces SIRT1, which decreases hMOF chromatin affinity and activity toward H4K16ac, resulting in decreased transcriptional expression of DNA repair genes independent of DNA methylation changes.\",\n      \"method\": \"RNA-seq, RRBS-seq, ChIP, siRNA knockdown\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq, ChIP, RRBS-seq; single lab with multiple methods\",\n      \"pmids\": [\"28808424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KAT8 regulates G2/M cell cycle arrest through AKT/ERK-cyclin D1 signaling. KAT8 inhibition led to p53 induction and subsequently reduced Bcl-2 expression in lung cancer cells.\",\n      \"method\": \"RNAi screen, Western blot, flow cytometry, siRNA knockdown\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNAi screen with limited mechanistic follow-up; single lab, limited methods reported in abstract\",\n      \"pmids\": [\"23638218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"hMOF regulates the expression of SIRT6 and its downstream genes in hepatocellular carcinoma cells. hMOF knockdown promotes HCC growth while overexpression reduces it, and the effect is mechanistically linked to SIRT6 regulation.\",\n      \"method\": \"siRNA knockdown, overexpression, ChIP (implied), in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown/overexpression with mechanistic link to SIRT6, but limited biochemical detail in abstract\",\n      \"pmids\": [\"25181338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MOF directly binds and maintains expression of cell cycle progression genes in proliferating cells (via NSL complex) but is dispensable for terminally differentiated podocytes under physiological conditions. Under injury stress, MOF is critical for podocyte maintenance, with genome-wide analysis revealing MOF directly binds lysosome, endocytosis, and vacuole pathway genes.\",\n      \"method\": \"Conditional knockout, ChIP-seq, RNA-seq, genome-wide expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout, ChIP-seq, RNA-seq; single lab, multiple methods\",\n      \"pmids\": [\"26387537\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT8 (hMOF/MYST1) is a MYST-family lysine acetyltransferase that, as part of the MSL complex, catalyzes the bulk of H4K16 acetylation via a ping-pong kinetic mechanism (Ac-CoA binding first, dependent on K274 autoacetylation for stability and activity), and as part of the NSL complex catalyzes H4K5ac and H4K8ac to support housekeeping gene transcription; beyond histones, KAT8 acetylates numerous non-histone substrates including IRF3 (suppressing antiviral immunity), Nrf2 (promoting nuclear retention), LSD1 (inhibiting EMT), DBC1 (regulating SirT1 activity), PRDX1 (controlling macrophage redox signaling), COX17 (supporting mitochondrial complex IV), and ATP5B (regulating mitochondrial energy metabolism), and additionally acts as a lactyltransferase/butyrylation writer for targets including eEF1A2 and HSP90; KAT8 activity is regulated by SIRT1-mediated deacetylation (inhibiting activity and promoting degradation), USP10-mediated deubiquitination (stabilizing the protein), and autoacetylation at K274, while its subcellular distribution spans both the nucleus and mitochondria, the latter pool being dependent on KANSL3 and required for oxidative phosphorylation and mtDNA transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAT8 (hMOF/MYST1) is a MYST-family lysine acetyltransferase that controls chromatin state and gene expression principally through histone H4 acetylation, and additionally acts on a broad set of non-histone substrates to regulate genome stability, redox balance, immunity, and mitochondrial function [#0, #5]. It catalyzes the bulk of cellular H4K16 acetylation as part of the MSL complex (with partners including hMSL3), while in the NSL complex it deposits H4K5ac and H4K8ac to drive transcription initiation at housekeeping gene promoters; depletion experiments show the NSL function is essential for cell survival whereas MSL/H4K16ac is dispensable for proliferation and chromatin accessibility [#0, #5]. Its catalytic mechanism is ping-pong, with acetyl-CoA binding first followed by substrate, and depends on autoacetylation of the MYST domain at K274, which stabilizes the enzyme and is required for activity—any substitution at K274 disorders the active-site loop and abolishes function [#9, #8, #7]. KAT8 is genetically essential in vivo: its loss blocks embryonic development past the blastocyst stage with specific failure of H4K16ac and induction of apoptosis [#2], and tissue-specific deletion impairs oocyte and trophoblast development, the latter via H4K16ac-dependent control of CDX2 [#21, #31]. Through H4K16ac it couples chromatin to the DNA-damage response, interacting with ATM and supporting ATM activation and repair after ionizing radiation [#1, #0], and regulates RNA Pol II pause release via BRD4/pTEFb recruitment [#15]. KAT8 also extends acetylation to non-histone targets to tune diverse pathways: it acetylates IRF3 to suppress type-I interferon responses [#10], Nrf2 to promote its nuclear retention and antioxidant gene expression [#12], LSD1 to restrain EMT [#14], and DBC1 to modulate SirT1 activity [#13]. A distinct mitochondrial pool, dependent on the NSL component KANSL3, binds mtDNA and is required for oxidative phosphorylation and respiratory gene transcription, with catalytic activity necessary for rescue [#4]; in mitochondria KAT8 acetylates the complex IV assembly factor COX17 and ATP5B to govern respiration and energy metabolism [#18, #33]. KAT8 itself is regulated by SIRT1-mediated deacetylation of its MYST domain, which inhibits activity and promotes ubiquitin-dependent degradation, and by USP10-mediated deubiquitination that stabilizes the protein [#7, #6, #28]. Beyond classical acetylation, KAT8 also functions as a lactyltransferase and butyrylation writer for substrates including eEF1A2 and HSP90 [#19, #35]. KAT8 contributes to malignancy, supporting MLL-AF9-driven leukemogenesis in a catalytic-activity-dependent manner [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established KAT8 as the enzyme responsible for the bulk of mammalian H4K16 acetylation and linked it physically and functionally to the DNA-damage response.\",\n      \"evidence\": \"siRNA knockdown with mass spectrometry of endogenous histones, Co-IP with hMSL3 and ATM, kinase and DNA repair assays in human cells\",\n      \"pmids\": [\"16024812\", \"15923642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which complex (MSL vs NSL) drives the repair phenotype\", \"Mechanism of ATM activation by H4K16ac left structural\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that KAT8 is non-redundantly required for development and that its function is specific to H4K16, not other histone lysines.\",\n      \"evidence\": \"Mof-null/conditional knockout mouse embryos with immunofluorescence, Western blot, and caspase-3 assays; gene-specific TMS1 ChIP studies\",\n      \"pmids\": [\"18541669\", \"18701507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate chromatin vs non-histone roles in lethality\", \"Downstream gene programs underlying apoptosis not fully mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined autoacetylation at K274 in the MYST domain as a regulatory switch and SIRT1 as its eraser controlling chromatin recruitment.\",\n      \"evidence\": \"In vitro acetylation and nucleosome-binding assays, Co-IP, and ChIP\",\n      \"pmids\": [\"21502975\", \"21321083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autoacetylation is intramolecular or intermolecular not settled\", \"Quantitative contribution of autoacetylation vs SIRT1 in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed SIRT1 deacetylation of the MYST domain inhibits KAT8 activity and triggers its degradation, coupling enzyme turnover to DNA damage.\",\n      \"evidence\": \"In vitro deacetylation, mutagenesis of target lysines, ubiquitination and DSB repair assays\",\n      \"pmids\": [\"22586264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating degradation not identified\", \"Kinetics of transient SIRT1 dissociation after damage not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected KAT8/H4K16ac to autophagy outcome and to non-histone control of SirT1 activity via DBC1 acetylation.\",\n      \"evidence\": \"Genome-wide ChIP-seq, siRNA knockdown, viability assays; in vitro DBC1 acetylation with mutagenesis\",\n      \"pmids\": [\"23863932\", \"24126058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering KAT8 downregulation during autophagy not fully defined\", \"Interplay between chromatin and DBC1 routes not integrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the enzymatic mechanism as ordered ping-pong with acetyl-CoA binding first, providing a kinetic framework and inhibitor basis.\",\n      \"evidence\": \"Enzyme kinetics and isothermal titration calorimetry with anacardic acid inhibitor analysis\",\n      \"pmids\": [\"26505788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done with isolated enzyme, not in complex context\", \"Substrate selectivity within MSL vs NSL not addressed kinetically\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a catalytically required mitochondrial pool of KAT8 controlling oxidative phosphorylation and mtDNA transcription, and structurally explained K274 dependence.\",\n      \"evidence\": \"Subcellular fractionation, ChIP on mtDNA, cardiac conditional knockout, catalytic-mutant rescue; X-ray crystallography of K274P mutant\",\n      \"pmids\": [\"27768893\", \"27382063\", \"27292636\", \"24571482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of KAT8 mitochondrial import not defined\", \"Mitochondrial substrates incompletely catalogued at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended KAT8 function to innate immunity by showing direct IRF3 acetylation suppresses type-I interferon responses.\",\n      \"evidence\": \"Co-IP, in vitro acetylation, ChIP, and mouse viral challenge\",\n      \"pmids\": [\"30842237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear vs cytoplasmic KAT8 acts on IRF3 unclear\", \"Complex dependence of IRF3 acetylation not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Separated KAT8 functions by complex: NSL-driven H4K5/K8ac is essential for housekeeping transcription whereas MSL-driven H4K16ac is dispensable for proliferation.\",\n      \"evidence\": \"Auxin-inducible degron depletion with mass spectrometry, ATAC-seq, RNA-seq, ChIP-seq; fibrosis ChIP/rescue work\",\n      \"pmids\": [\"33657400\", \"34285225\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How complex partitioning is regulated in cells not resolved\", \"Reconciliation with earlier H4K16ac-essential phenotypes incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the substrate and modification repertoire to mitochondrial COX17 acetylation and to condensate-based IRF1 acetylation controlling PD-L1, plus butyrylation of HSP90.\",\n      \"evidence\": \"In vitro acetylation, Co-IP, electron microscopy and acetyl-mimetic rescue; phase-separation assays with blocking peptide and tumor models; butyrylome profiling\",\n      \"pmids\": [\"37813994\", \"36894639\", \"37460462\", \"39207899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of substrate vs modification choice (acetyl/butyryl) unknown\", \"Physiological triggers for condensate formation incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified KAT8 as a lactyltransferase writer acting on eEF1A2, PCK2, and other targets, and confirmed USP10-mediated stabilization controlling its oncogenic output.\",\n      \"evidence\": \"Lactylome profiling, in vitro lactylation, Co-IP, ubiquitination assays, and KAT8 deletion/gene-edited mouse models\",\n      \"pmids\": [\"38359291\", \"39853940\", \"38317006\", \"39392752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Active-site basis for lactyl vs acetyl transfer not structurally defined\", \"How metabolic lactate levels gate KAT8 writer activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single MYST enzyme selects among acyl-CoA donors (acetyl, lactyl, butyryl), histone vs non-histone substrates, and nuclear vs mitochondrial compartments remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model distinguishing donor selectivity\", \"Regulation of compartmental partitioning between nucleus and mitochondria undefined\", \"Rules governing complex assembly (MSL vs NSL) in different cell types unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 10, 12, 13, 14, 18, 33]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8, 9, 19, 35]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 21, 37]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 7, 15]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 18, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 12, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 6, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 12, 13, 18, 35]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 18, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\"MSL complex\", \"NSL complex\"],\n    \"partners\": [\"MSL3\", \"ATM\", \"SIRT1\", \"KANSL3\", \"IRF3\", \"USP10\", \"Nrf2\", \"LSD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}