{"gene":"HAT1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1998,"finding":"Human HAT1 holoenzyme was purified from 293 cells and shown to acetylate soluble (but not nucleosomal) histone H4 at Lys5 and Lys12, and histone H2A at Lys5. The holoenzyme consists of two subunits: the catalytic HAT1 subunit and p46, which binds core histones and greatly stimulates HAT1 acetyltransferase activity. Both p46 and the related p48 (CAF-1 small subunit) bind directly to helix 1 of histone H4, a region inaccessible in chromatin.","method":"Purification from human 293 cells, in vitro acetyltransferase assay on soluble vs. nucleosomal substrates, specific antibodies, direct binding assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, substrate specificity assay, direct binding assays, multiple orthogonal methods","pmids":["9427644"],"is_preprint":false},{"year":1998,"finding":"Crystal structure of yeast Hat1 in complex with acetyl-CoA solved at 2.3 Å resolution. Hat1 has an elongated curved structure with AcCoA bound in a cleft on the concave surface marking the active site, and a channel across the protein that is the likely histone substrate binding site. This structure established Hat1 as the founding paradigm for the GCN5-related N-acetyltransferase (GNAT) superfamily.","method":"X-ray crystallography at 2.3 Å resolution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with bound cofactor, functionally validated active site, replicated structural model used by many subsequent studies","pmids":["9727486"],"is_preprint":false},{"year":1998,"finding":"Yeast HAT1 and HAT2 are both required for two acetyltransferase activities: the cytoplasmic type B enzyme and a nuclear free-histone H4-specific acetyltransferase. Both complexes share the same 42 kDa HAT1 catalytic subunit but differ in molecular mass (cytoplasmic ~150 kDa; nuclear ~110 kDa), establishing HAT1 as a component of both cytoplasmic and nuclear acetyltransferase complexes.","method":"Genetic analysis using hat1, hat2, and gcn5 single and double yeast mutants; biochemical fractionation and activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistatic genetic analysis combined with biochemical fractionation and activity assays, replicated across multiple mutant strains","pmids":["9575221"],"is_preprint":false},{"year":1999,"finding":"The Xenopus Hat1 holoenzyme contains three components: the catalytic Hat1 subunit, RbAp48 (a phosphoprotein), and 14-3-3 proteins (which bind RbAp48 via its consensus phosphoserine recognition motif). The holoenzyme specifically acetylates free but not nucleosomal histone H4 and is localized in the oocyte nucleus where acetylated histones are stored. After oocyte maturation, Hat1 redistributes to the cytoplasm.","method":"Purification from Xenopus oocytes, biochemical fractionation, in vitro acetyltransferase assay, localization by cell fractionation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — purification of native complex, multiple components identified, in vitro activity assay, localization by fractionation, single lab","pmids":["10529179"],"is_preprint":false},{"year":2001,"finding":"HAT1 substrate specificity requires positively charged residues (Lys or Arg) at positions 8 and 16 of the H4 N-terminal tail; replacing Lys-8 and Lys-16 with glutamines abolishes acetylation. Phosphorylation of Ser-1 of H4 depresses acetylation by both yeast Hat1p and human HAT-B. Lys-12 of H4 is preferentially acetylated by human HAT-B. Prior acetylation of Lys-8 and Lys-16 of H4 prevents Hat1 from acetylating Lys-5 and Lys-12, demonstrating that pre-existing H4 acetylation regulates Hat1 activity.","method":"In vitro HAT assays using synthetic H4 N-terminal peptides with specific mutations and chemical modifications; yeast Hat1p and human HAT-B complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined synthetic substrates, multiple mutants tested, site-specific mechanistic conclusions supported by biochemical data","pmids":["11585814"],"is_preprint":false},{"year":2006,"finding":"Hat1 H4 tail interaction requires positively charged amino acids at positions 8 and 16 of H4; Lys-12 is preferentially acetylated by human HAT-B. Deletion of hat1 from fission yeast S. pombe causes increased sensitivity to the DNA-damaging agent MMS even without additional H3 tail mutations, demonstrating an evolutionarily conserved role for Hat1 in DNA damage repair.","method":"In vitro HAT assays on synthetic H4 peptides; genetic analysis in S. pombe hat1Δ strains with MMS sensitivity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — combined in vitro enzymatic analysis and genetic epistasis across two yeast species","pmids":["17052979"],"is_preprint":false},{"year":2012,"finding":"In S. pombe, Hat1 (Kat1) is associated with the RbAp46 homologue Mis16 (an essential protein). The Hat1 complex acetylates H4 Lys5 and Lys12. Deletion of hat1 alone (without additional H3 tail mutations) is sufficient to cause loss of silencing specifically at telomeres, and is accompanied by increased H4 acetylation in subtelomeric chromatin, establishing a direct link between Hat1, H4 acetylation, and repressed telomeric chromatin.","method":"Co-immunoprecipitation (Hat1-Mis16 interaction), in vitro acetyltransferase assay, genetic deletion of hat1, silencing assays at telomeres/centromeres/mating-type locus in S. pombe","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, in vitro activity assay, clean genetic KO with defined chromatin and silencing phenotype","pmids":["22771823"],"is_preprint":false},{"year":2014,"finding":"HAT1 acetylates the transcriptional repressor PLZF upon activation by CaMK2 signaling downstream of Toll-like receptor or TNF-α receptor stimulation. Acetylated PLZF assembles a repressor complex containing HDAC3 and NF-κB p50 that limits the NF-κB transcriptional response. Mutation of key residues in PLZF and HAT1, or reduction of CaMK2 activity, curtails control of inflammatory cytokine production.","method":"Co-immunoprecipitation, mutagenesis of key acetylation residues in PLZF and HAT1, kinase activity assays, cytokine measurement, genetic knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis with functional readout, single lab with multiple orthogonal methods","pmids":["25865065"],"is_preprint":false},{"year":2014,"finding":"Human HAT1 acetylates lysine 5 of histone H2A in vivo, in addition to H4 K5 and K12. Knockdown of HAT1 in HeLa cells (with abrogated Tip60 activity) reduces acetylation of H4-K5, H4-K12, and H2A-K5 in cytosolic and nuclear/insoluble nuclear protein fractions, and impairs colony-forming efficiency.","method":"shRNAmir-mediated knockdown of HAT1 in HeLa cells expressing catalytically dead Tip60, Western blotting of histone fractions","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific knockdown with competing enzyme disabled, multiple histone substrate sites assessed by Western blot in multiple fractions","pmids":["24682716"],"is_preprint":false},{"year":2015,"finding":"In Candida albicans, Hat1 (catalytic subunit of the NuB4 complex) is required for efficient repair of both exogenous and endogenous DNA damage, and its loss causes accumulation of DNA damage and a switch from yeast-like to pseudohyphal growth. Reduction of histone H4 levels phenocopies Hat1 loss, suggesting that insufficient H4 supply for chromatin deposition is the key functional consequence of Hat1 deficiency.","method":"Conditional Hat1 depletion, DNA damage assays (sensitivity to MMS, H2O2), morphological analysis, histone H4 reduction experiments","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple defined phenotypic readouts and genetic epistasis with H4 levels, single lab","pmids":["23075292"],"is_preprint":false},{"year":2015,"finding":"In Drosophila, Hat1 forms a novel complex with the histone chaperone Caf1/Rbap48 and CENP-A/H4. Hat1 is required for proper CENP-A loading into chromatin, as Hat1 knockdown in S2 cells reduces incorporation of newly synthesized CENP-A. CENP-A/Cid interacts with the Hat1 complex via an N-terminal region that is acetylated in cytoplasmic but not nuclear CENP-A, suggesting a HAT activity-independent escort function for Hat1.","method":"Co-immunoprecipitation to define complex, RNAi knockdown in S2 cells with CENP-A loading assay, acetylation site mapping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP defining new complex, RNAi knockdown with functional centromere loading readout, single lab","pmids":["26586808"],"is_preprint":false},{"year":2017,"finding":"AMPK directly phosphorylates HAT1, resulting in its activation. AMPK-mediated HAT1 activation promotes a more relaxed chromatin structure favoring transcription of nuclear genes involved in mitochondrial biogenesis (e.g., PGC-1α, Tfam, UCP2/3). These effects were observed in human umbilical vein cells treated with pharmacological AMPK activators or pulsatile shear stress, and in aortas of mice given AMPK activators (requiring AMPK2α).","method":"Identification of AMPK consensus phosphorylation sequences in HAT1; phosphorylation assays; nucleosome remodeling and gene expression assays in endothelial cells and mouse aortas; pharmacological AMPK activation","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro phosphorylation assay combined with cellular and in vivo functional readouts, single lab, multiple orthogonal methods","pmids":["28143904"],"is_preprint":false},{"year":2019,"finding":"HAT1 binds specifically to promoters of histone H4 genes (in addition to its canonical cytoplasmic acetyltransferase role), and HAT1-dependent transcription of H4 genes requires an acetate-sensitive promoter element. HAT1 is critical for S-phase progression and maintenance of H3K9 acetylation at proliferation-associated genes including histone genes, establishing a feedforward circuit where HAT1 captures acetyl groups on nascent histones and drives H4 production.","method":"ChIP-seq (HAT1 complex at H4 gene promoters), S-phase progression assays, H3K9ac ChIP, metabolic acetate perturbation, genetic knockdown/overexpression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, functional S-phase assays, acetate-sensitive promoter element validated, multiple orthogonal methods in a single rigorous study","pmids":["31278053"],"is_preprint":false},{"year":2019,"finding":"Loss of HAT1 in conditional mouse knockout leads to early-onset aging phenotypes and mitochondrial defects. Hat1-/- MEFs exhibit mitochondrial dysfunction; Hat1+/- MEFs show elevated ROS and early senescence with high p21 levels. Hat1 protein localizes to mitochondria, suggesting a direct role in acetylation of mitochondrial proteins.","method":"Conditional mouse knockout, MEF isolation, ROS assays, senescence assays (p21, β-galactosidase), mitochondrial function assays, subcellular fractionation (mitochondrial localization)","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO model, multiple orthogonal cellular phenotypic readouts, direct localization by fractionation, replicated across Hat1+/- and Hat1-/- cells","pmids":["31290578"],"is_preprint":false},{"year":2019,"finding":"HAT1 promotes assembly and epigenetic regulation of HBV cccDNA minichromosome. HAT1 depletion reduces HBV replication and cccDNA accumulation, impairs histone H3/H4 assembly and deposition of HBx and p300 onto cccDNA. HAT1 modifies acetylation of H3K27, H4K5, and H4K12 on cccDNA minichromosome. lncRNA HULC scaffolds a HAT1/HULC/HBc complex responsible for cccDNA modification. HBV activates HAT1 through HBx-co-activated Sp1 in a positive feedback manner.","method":"HAT1 knockdown, cccDNA-ChIP, confocal assays, RIP assays, RNA pulldown, Southern blot in liver-chimeric mouse model and hepatocyte cell lines","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, pulldown) in a complex model system, single lab","pmids":["31695772"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, Hat1 is the main acetyltransferase responsible for H4-K5 and H4-K12 acetylation in embryos. However, loss of Hat1 (and H4-K5/K12 acetylation) does not impair nuclear transport of histone H4, indicating these marks are not required for H4 nuclear import. Loss of Hat1 causes dysregulation of over 2000 genes, implying a broad role in developmental transcriptional programs.","method":"Hat1 loss-of-function mutant generation in Drosophila, Western blotting for H4K5ac/H4K12ac, nuclear localization assay for H4 (including K5R/K12R double point mutants), RNA-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (protein acetylation, localization, transcriptomics), single lab","pmids":["31784689"],"is_preprint":false},{"year":2020,"finding":"Proteomics of Hat1+/+ vs Hat1-/- mouse embryonic fibroblasts identified 65 proteins with ≥2.5-fold decreased acetylation in Hat1-/- cells. The most affected was the autoregulatory loop of CBP (CREB-binding protein), which decreased up to 20-fold. Hat1-dependent acetylation was found on transcriptional regulators (p53), chromatin structural proteins, and mitochondrial proteins. Hat1 mitochondrial localization (by fractionation) supports a direct role in mitochondrial protein acetylation.","method":"Unbiased proteomics (label-free quantitation), acetyllysine affinity purification/MS, Hat1+/+ vs Hat1-/- MEFs, subcellular fractionation","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomics with affinity enrichment, genetic KO comparison, multiple substrate identifications, mitochondrial localization confirmed by fractionation","pmids":["32081014"],"is_preprint":false},{"year":2021,"finding":"HAT1 acts as a methacryltransferase, catalyzing a newly discovered histone post-translational modification, lysine methacrylation (Kmea). Biochemical studies show that HAT1 writes histone Kmea marks and SIRT2 acts as the corresponding de-methacrylase. 27 Kmea-modified histone sites were identified in HeLa cells.","method":"Affinity enrichment with pan-Kmea antibody, mass spectrometry, in vitro enzymatic assays with HAT1 and SIRT2, antibody validation with chemical approaches","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay establishing writer/eraser, MS identification of sites, antibody validation with chemical methods, single lab with multiple orthogonal approaches","pmids":["34961760"],"is_preprint":false},{"year":2021,"finding":"Loss of HAT1 results in loss of accessibility of large megabase-scale heterochromatin domains (HAT1-dependent Accessibility Domains, HADs) comprising ~10% of the mouse genome. HAT1 globally represses H3K9me3 levels, and HADs correspond to regions with HAT1-dependent increases in H3K9me3 peak density. HADs overlap with a subset of Lamin-Associated Domains (LADs), and HAT1 is required to maintain nuclear structure and integrity.","method":"ATAC-seq (chromatin accessibility), H3K9me3 ChIP-seq, HAT1 knockout MEFs, LAD mapping, nuclear structure imaging","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genome-wide orthogonal assays (ATAC-seq, ChIP-seq), clean KO model, mechanistic link between HAT1 and heterochromatin/LAD structure established","pmids":["34788845"],"is_preprint":false},{"year":2022,"finding":"HAT1 directly promotes acetylation of the non-histone substrate ACSL4 at lysine 383, enhancing ACSL4 protein stability by inhibiting F-box protein FBXO10-mediated K48-linked ubiquitination. SIRT3 mediates deacetylation of ACSL4, while HDAC2 enhances ACSL4 acetylation indirectly by inhibiting SIRT3 transcription.","method":"Co-immunoprecipitation (HAT1-ACSL4 interaction), in vitro acetylation assay, site-directed mutagenesis (K383), ubiquitination assay, in vitro deacetylation assay with SIRT3","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro acetylation and deacetylation assays, mutagenesis of target site, ubiquitination assay, single lab","pmids":["40050614"],"is_preprint":false},{"year":2022,"finding":"HAT1 directly acetylates HIF2A at K512 and K596, stabilizing HIF2A under both normoxia and hypoxia. Acetylation-mimic mutations (K512Q or K596Q) restore HIF2A stability in HAT1-silenced cells. HAT1 and HIF2A interact with each other and co-occupy the VEGFA promoter. The HAT1-HIF2A axis is essential for hypoxia-promoted cancer stem cell maintenance.","method":"Co-immunoprecipitation (HAT1-HIF2A), site-directed mutagenesis of acetylation sites (K512, K596), HAT1 silencing with HIF2A stability assays, ChIP (HAT1 and HIF2A at VEGFA promoter), cancer stem cell assays","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, mutagenesis of target sites, ChIP validation, functional stem cell assays, single lab with multiple orthogonal methods","pmids":["36410688"],"is_preprint":false},{"year":2022,"finding":"The crystal structure of the Hat1-Hat2 acetyltransferase complex bound to Asf1-H3-H4 reveals that the core domains of both H3 and H4 interact with Hat1 and Hat2, and the N-terminal tail of H3 makes extensive contact with Hat2. This expands the known histone-protein interaction landscape and implicates Hat2/RbAp46/48 in passing histones between chaperones.","method":"Cryo-EM/X-ray crystallography of the Hat1-Hat2-Asf1-H3-H4 complex","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of multi-component complex with full-length histones, detailed interaction map, single lab but rigorous structural data","pmids":["35393344"],"is_preprint":false},{"year":2022,"finding":"The FOXP3/HAT1 axis controls CCR4 expression in Tregs via epigenetic regulation of the CCR4 promoter. FOXP3 recruits HAT1 to the CCR4 promoter, and this complex mediates permissive (H3K23ac, H3K27ac) or repressive (H3K14ac, H3K18ac) acetylation of histone H3 to regulate CCR4 gene expression in Tregs.","method":"Co-immunoprecipitation (FOXP3-HAT1), ChIP at CCR4 promoter for FOXP3 and histone acetylation marks, overexpression and knockdown in Treg models, murine tumor models","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP establishing promoter complex and histone marks, in vivo tumor model validation, single lab","pmids":["35222362"],"is_preprint":false},{"year":2010,"finding":"Human HAT1 has two isoforms: isoform a (418 aa) localized exclusively in the nuclear matrix, and isoform b (334 aa) found in cytoplasm, nucleoplasm, chromatin, and nuclear matrix of normal human keratinocytes. Cells undergoing mitosis have elevated nuclear Hat1. Exposure to heavy-ion particles or H2O2 triggers increased nuclear Hat1 staining regulated by PI3K and MAPK signaling pathways.","method":"Immunohistochemistry, subcellular fractionation, immunofluorescence microscopy in normal human keratinocytes; pharmacological inhibition of PI3K and MAPK","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation and immunostaining in multiple cell states, pathway involvement by pharmacological inhibition, single lab","pmids":["20148353"],"is_preprint":false},{"year":2021,"finding":"HAT1 activates YTHDF2 transcription through histone acetylation of the YTHDF2 promoter in retinal cells. YTHDF2 in turn triggers m6A-dependent instability and degradation of ITGB1 mRNA. The resulting suppression of ITGB1 inhibits the FAK/PI3K/AKT signaling pathway in retinal Müller cells and endothelial cells.","method":"HAT1 overexpression/knockdown, ChIP (histone acetylation at YTHDF2 promoter), mRNA stability assays, pathway (FAK/PI3K/AKT) analysis by Western blotting, in vivo STZ-induced DR mouse model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating promoter acetylation, mRNA stability assays, in vivo validation, single lab","pmids":["34098071"],"is_preprint":false},{"year":2023,"finding":"In rice, HAT1 (HAG704) acetylates histone H4K5 and H4K16, and H4K5 acetylation activity requires the ACL subunit A2 (ACLA2). ACL and HAT1 form a nuclear module; ACLA2 is present in nuclear condensates and is required for nuclear acetyl-CoA accumulation. Loss of either ACLA2 or HAT1 impairs cell division in developing endosperm, reduces H4K5ac at overlapping genomic regions, and causes S-phase stagnation.","method":"Co-IP (ACLA2-HAT1 interaction), in vitro acetyltransferase assay (H4K5, H4K16), H4K5ac ChIP-seq, cell cycle analysis, genetic mutations in rice endosperm","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro enzymatic assay, ChIP-seq, cell cycle phenotype, single lab with multiple orthogonal methods (rice ortholog)","pmids":["37277331"],"is_preprint":false},{"year":2025,"finding":"Nuclear ACLY recruits and physically interacts with HAT1 (and P300) in oocytes and early embryos, supplying acetyl-CoA for histone acetylation to activate transcription required for embryogenesis. AKT-mediated phosphorylation of ACLY at Thr447/Ser451/Ser455 drives its nuclear translocation and facilitates its interaction with HAT1 and P300.","method":"Co-IP (ACLY-HAT1 interaction), maternal knockout, zygotic KO, histone acetylation assays, subcellular fractionation, AKT inhibitor studies","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing physical interaction, multiple genetic models, functional histone acetylation readout, single lab","pmids":["40470746"],"is_preprint":false},{"year":2018,"finding":"HAT1 is a component of a novel RIP1/3-SIRT1/2-HAT1/4 complex identified by mass spectrometry and co-immunoprecipitation. Mass spectrometry identified five acetylation sites in the kinase and death domain of RIP1, and a pan-SIRT inhibitor increases RIP1 acetylation, with acetylation of the RIP1 death domain modulating cell death.","method":"Co-immunoprecipitation, mass spectrometry (complex identification and acetylation site mapping), mutagenesis of acetylated lysines in RIP1, enzymatic assays","journal":"Clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — complex identified by MS and co-IP, mechanistic link of HAT1 specifically (vs HAT4 or SIRTs) within the complex is not separately established","pmids":["29535128"],"is_preprint":false},{"year":2023,"finding":"HMGB1 physically interacts with SET and HAT1 in lung adenocarcinoma cells to form a HMGB1/SET/HAT1 complex that inhibits H3K9 and H3K27 acetylation, represses SASH1 expression, and thereby promotes glycolysis and metastasis.","method":"Co-immunoprecipitation (HMGB1, SET, HAT1), H3K9ac/H3K27ac Western blotting, SASH1 ChIP assays, functional glycolysis and invasion assays, in vivo xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing complex, ChIP for histone marks at SASH1 promoter, in vitro and in vivo functional readouts, single lab","pmids":["37794134"],"is_preprint":false},{"year":2021,"finding":"In C. elegans embryos, HAT-1 (with RbAp46/48LIN-53) is required for chromatinization and de novo centromere (CENP-AHCP-3) formation on artificial chromosomes. Depletion of HAT-1 causes loss of both CENP-AHCP-3 and Mis18BP1KNL-2 initial deposition at de novo centromeres on artificial chromosomes, distinguishing this from centromere maintenance on endogenous chromosomes.","method":"RNAi depletion of HAT-1 and LIN-53 in C. elegans embryos, immunofluorescence for CENP-A, Mis18BP1, H3K9ac/H4K5ac/H4K12ac, artificial chromosome segregation assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi in defined developmental context, multiple centromere component readouts, functional segregation assay, single lab","pmids":["33872374"],"is_preprint":false}],"current_model":"HAT1 (KAT1) is a type B histone acetyltransferase that forms a nuclear/cytoplasmic complex with RbAp46/48 (and in some contexts 14-3-3 proteins) to acetylate newly synthesized histone H4 at Lys5 and Lys12 (and H2A at Lys5), a modification that is required for replication-coupled chromatin assembly, epigenetic inheritance of heterochromatin (including LAD-associated domains and telomeric silencing), DNA damage repair, CENP-A loading, S-phase progression, and H4 gene transcription via promoter binding; beyond histones, HAT1 also catalyzes lysine methacrylation and acetylates non-histone substrates including PLZF (modulating NF-κB signaling), HIF2A (stabilizing hypoxic response), and ACSL4 (enhancing ferroptosis sensitivity), and its activity is regulated by AMPK-mediated phosphorylation and by interaction with metabolic enzymes (ACL/ACLY) that supply local acetyl-CoA."},"narrative":{"mechanistic_narrative":"HAT1 is the catalytic subunit of the type B histone acetyltransferase that acetylates newly synthesized, soluble (non-nucleosomal) histone H4 at Lys5 and Lys12 and H2A at Lys5, the committed step that primes nascent histones for replication-coupled chromatin assembly [PMID:9427644, PMID:24682716]. It functions as a holoenzyme with the histone-binding chaperone subunit RbAp46/48 (yeast Hat2, S. pombe Mis16), which binds helix 1 of H4 and core histones to greatly stimulate catalysis, and in some contexts associates with 14-3-3 proteins via phosphorylated RbAp48 [PMID:9427644, PMID:10529179, PMID:22771823]; structural work defined Hat1 as the founding member of the GNAT superfamily and mapped how the Hat1-RbAp46/48 module engages H3-H4 handed off from the chaperone Asf1 [PMID:9727486, PMID:35393344]. Substrate selection is governed by the H4 tail: acetylation requires positively charged residues at H4 positions 8 and 16, is blocked by Ser1 phosphorylation, and is precluded by prior acetylation of Lys8/Lys16, so existing modifications gate HAT1 activity [PMID:11585814]. Through this histone-deposition activity HAT1 supports diverse genome functions — epigenetic maintenance of repressed telomeric and large heterochromatin/LAD-associated domains, global restraint of H3K9me3, de novo and replication-coupled CENP-A loading at centromeres, DNA damage repair, and S-phase progression coupled to a feedforward circuit in which HAT1 binds H4 gene promoters to drive histone production [PMID:22771823, PMID:34788845, PMID:26586808, PMID:33872374, PMID:17052979, PMID:31278053]. HAT1 activity is integrated with metabolism and signaling: AMPK directly phosphorylates and activates it, and it partners with nuclear acetyl-CoA-generating enzymes (ACL/ACLY) to obtain local cofactor for histone acetylation during transcriptional activation and development [PMID:28143904, PMID:37277331, PMID:40470746]. Beyond histones HAT1 acetylates non-histone substrates including PLZF to assemble an HDAC3/NF-κB p50 repressor that limits inflammatory signaling, HIF2A (K512/K596) to stabilize the hypoxic response, and ACSL4 (K383) to block its ubiquitin-mediated degradation, and it writes a distinct histone mark, lysine methacrylation, opposed by SIRT2 [PMID:25865065, PMID:36410688, PMID:40050614, PMID:34961760]. Loss of HAT1 in mice produces mitochondrial dysfunction, elevated ROS, and early senescence/aging phenotypes, consistent with its localization to mitochondria and a broad non-histone acetylome including CBP and p53 [PMID:31290578, PMID:32081014].","teleology":[{"year":1998,"claim":"Established the core enzymatic identity of HAT1 as a type B HAT that modifies free histones, defining its substrate sites and its dependence on an accessory histone-binding subunit.","evidence":"Purification of the human holoenzyme from 293 cells with in vitro acetyltransferase assays on soluble vs. nucleosomal substrates and direct binding assays; crystal structure of yeast Hat1-acetyl-CoA; genetic analysis of yeast hat1/hat2 mutants","pmids":["9427644","9727486","9575221"],"confidence":"High","gaps":["Did not explain how the cytoplasmic deposition product is transferred to chromatin","Mechanism distinguishing cytoplasmic from nuclear complex forms unresolved"]},{"year":1999,"claim":"Resolved the native holoenzyme composition and its regulated subcellular partitioning, linking HAT1 to histone storage pools.","evidence":"Purification from Xenopus oocytes identifying Hat1, RbAp48, and 14-3-3; in vitro activity assays and localization by fractionation across oocyte maturation","pmids":["10529179"],"confidence":"High","gaps":["Functional role of 14-3-3 in catalysis or trafficking not defined","Trigger for nuclear-to-cytoplasmic redistribution unknown"]},{"year":2001,"claim":"Defined the recognition rules and combinatorial regulation of HAT1 by the H4 tail, showing pre-existing marks gate its activity.","evidence":"In vitro HAT assays on synthetic H4 peptides bearing point mutations and chemical modifications, using yeast Hat1p and human HAT-B","pmids":["11585814"],"confidence":"High","gaps":["In vivo relevance of Ser1-phosphorylation crosstalk not tested","Did not address selectivity on H2A"]},{"year":2006,"claim":"Connected HAT1 to genome maintenance by showing a conserved requirement in DNA damage repair independent of H3 tail modification.","evidence":"In vitro peptide HAT assays plus MMS sensitivity in S. pombe hat1Δ strains; later extended in C. albicans with H4-level epistasis","pmids":["17052979","23075292"],"confidence":"Medium","gaps":["Whether repair defect is solely due to deficient H4 supply vs direct repair role unresolved","Specific repair pathway affected not pinpointed"]},{"year":2012,"claim":"Demonstrated a direct epigenetic role for HAT1 in heterochromatic silencing, linking its H4 acetylation activity to repressed telomeric chromatin.","evidence":"Reciprocal Hat1-Mis16 co-IP, in vitro acetyltransferase assays, and silencing assays in S. pombe hat1 deletion strains","pmids":["22771823"],"confidence":"High","gaps":["How an activating acetylation mark promotes silencing mechanistically not explained","Mammalian generality not addressed in this study"]},{"year":2014,"claim":"Extended HAT1 substrate range to H2A K5 in vivo and to non-histone targets, opening a non-chromatin signaling function via PLZF.","evidence":"shRNA knockdown with histone fraction Westerns (Tip60-disabled HeLa); co-IP, residue mutagenesis, and cytokine readouts for PLZF/CaMK2/NF-κB","pmids":["24682716","25865065"],"confidence":"Medium","gaps":["Direct vs indirect H2A-K5 acetylation by HAT1 not fully separated from compensating enzymes","Generality of PLZF axis beyond TLR/TNF stimulation unknown"]},{"year":2015,"claim":"Implicated HAT1 in centromere identity by showing a role in CENP-A loading, partly via a chaperone-escort function distinct from catalysis.","evidence":"Co-IP defining a Hat1-Caf1/Rbap48-CENP-A/H4 complex and RNAi CENP-A loading assays in Drosophila S2 cells; later C. elegans de novo centromere assays","pmids":["26586808","33872374"],"confidence":"Medium","gaps":["Separation of catalytic vs escort contributions to CENP-A deposition incomplete","Whether endogenous centromere maintenance requires HAT1 not established"]},{"year":2017,"claim":"Identified upstream signaling control of HAT1, linking AMPK phosphorylation to HAT1-driven chromatin relaxation and mitochondrial biogenesis gene expression.","evidence":"Identification of AMPK consensus sites, phosphorylation and nucleosome/gene-expression assays in endothelial cells and mouse aortas with pharmacological AMPK activation","pmids":["28143904"],"confidence":"Medium","gaps":["Phosphosite-specific functional mapping incomplete","Direct enzymatic consequence of phosphorylation on acetyl-transfer kinetics not measured"]},{"year":2019,"claim":"Defined a feedforward transcriptional circuit and physiological consequence of HAT1 loss, tying nascent-histone acetylation to H4 gene production, S-phase, and organismal aging.","evidence":"ChIP-seq of HAT1 at H4 promoters with acetate-sensitive element analysis and S-phase assays; conditional mouse KO with ROS, senescence, and mitochondrial assays; Drosophila LOF transcriptomics","pmids":["31278053","31290578","31784689"],"confidence":"High","gaps":["Whether H4-K5/K12 marks themselves are dispensable for H4 import (per Drosophila) vs required for downstream assembly not reconciled","Mechanism linking mitochondrial localization to acetylation targets not fully resolved"]},{"year":2020,"claim":"Mapped the HAT1-dependent acetylome, revealing broad non-histone substrates including CBP and p53 and supporting a direct mitochondrial role.","evidence":"Label-free quantitative proteomics with acetyllysine affinity-MS comparing Hat1+/+ and Hat1-/- MEFs plus subcellular fractionation","pmids":["32081014"],"confidence":"High","gaps":["Direct vs indirect acetylation of identified targets not validated site by site","Functional consequences of mitochondrial protein acetylation undefined"]},{"year":2021,"claim":"Revealed genome-scale chromatin architecture functions and an unexpected enzymatic capability for HAT1.","evidence":"ATAC-seq and H3K9me3 ChIP-seq in HAT1-KO MEFs with LAD mapping and nuclear imaging; pan-Kmea MS and in vitro writer/eraser assays with HAT1/SIRT2","pmids":["34788845","34961760"],"confidence":"High","gaps":["How HAT1 represses H3K9me3 globally (direct vs indirect) not mechanistically resolved","Physiological role of histone methacrylation undefined"]},{"year":2022,"claim":"Consolidated structural understanding of histone hand-off and broadened the non-histone substrate set to stress and metabolic regulators.","evidence":"Structure of Hat1-Hat2-Asf1-H3-H4; co-IP/mutagenesis/ChIP defining HIF2A (K512/K596) stabilization and ACSL4 (K383) stabilization, and FOXP3-recruited promoter acetylation","pmids":["35393344","36410688","40050614","35222362"],"confidence":"Medium","gaps":["In vivo stoichiometry of non-histone acetylation events unclear","Context determinants directing HAT1 to histone vs non-histone substrates unknown"]},{"year":2023,"claim":"Established metabolic coupling of HAT1 to local acetyl-CoA supply via ACL/ACLY, integrating nutrient state with histone acetylation and cell division.","evidence":"Co-IP, in vitro HAT assays, and H4K5ac ChIP-seq linking HAT1 to ACLA2 in rice endosperm; ACLY-HAT1 interaction in oocytes/embryos with AKT-driven nuclear translocation","pmids":["37277331","40470746"],"confidence":"Medium","gaps":["Direct demonstration of channeled acetyl-CoA to HAT1 active site lacking","Conservation of ACLY-HAT1 module in somatic mammalian cells not established"]},{"year":null,"claim":"How HAT1's many reported non-histone substrates and disease-associated complexes are mechanistically prioritized in vivo, and how its mitochondrial functions relate to its canonical histone-deposition role, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating cytoplasmic deposition, nuclear transcriptional, and mitochondrial roles","Substrate-selection determinants between histone and non-histone targets unknown","No human Mendelian disease link established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,7,19,20]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4,21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[13,16]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[12,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,10,29]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[12,22]}],"complexes":["HAT1-RbAp46/48 (type B HAT-B) holoenzyme","NuB4 complex","Hat1-RbAp48-14-3-3 holoenzyme","HMGB1/SET/HAT1 complex"],"partners":["RBBP7","RBBP4","ACLY","HIF2A","ACSL4","PLZF","FOXP3","CENPA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14929","full_name":"Histone acetyltransferase type B catalytic subunit","aliases":["Histone acetyltransferase 1","Histone methacryltransferase HAT1"],"length_aa":419,"mass_kda":49.5,"function":"Histone acetyltransferase that plays a role in different biological processes including cell cycle progression, glucose metabolism, histone production or DNA damage repair (PubMed:20953179, PubMed:23653357, PubMed:31278053, PubMed:32081014). Coordinates histone production and acetylation via H4 promoter binding (PubMed:31278053). Acetylates histone H4 at 'Lys-5' (H4K5ac) and 'Lys-12' (H4K12ac) and, to a lesser extent, histone H2A at 'Lys-5' (H2AK5ac) (PubMed:11585814, PubMed:22615379). Drives H4 production by chromatin binding to support chromatin replication and acetylation. Since transcription of H4 genes is tightly coupled to S-phase, plays an important role in S-phase entry and progression (PubMed:31278053). Promotes homologous recombination in DNA repair by facilitating histone turnover and incorporation of acetylated H3.3 at sites of double-strand breaks (PubMed:23653357). In addition, acetylates other substrates such as chromatin-related proteins (PubMed:32081014). Also acetylates RSAD2 which mediates the interaction of ubiquitin ligase UBE4A with RSAD2 leading to RSAD2 ubiquitination and subsequent degradation (PubMed:31812350). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as 2-methylpropenoyl-CoA (methacryl-CoA), and is able to mediate histone methacrylation (PubMed:34961760) (Microbial infection) Contributes to hepatitis B virus (HBV) replication by acetylating histone H4 at the sites of 'Lys-5' and 'Lys-12' on the covalently closed circular DNA (cccDNA) minichromosome leading to its accumulation within the host cell","subcellular_location":"Cytoplasm; Nucleus; Nucleus matrix; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/O14929/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HAT1","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NMD3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HAT1","total_profiled":1310},"omim":[{"mim_id":"606543","title":"HISTONE DEACETYLASE 9; HDAC9","url":"https://www.omim.org/entry/606543"},{"mim_id":"605315","title":"HISTONE DEACETYLASE 5; HDAC5","url":"https://www.omim.org/entry/605315"},{"mim_id":"605314","title":"HISTONE DEACETYLASE 4; HDAC4","url":"https://www.omim.org/entry/605314"},{"mim_id":"603053","title":"HISTONE ACETYLTRANSFERASE 1; HAT1","url":"https://www.omim.org/entry/603053"},{"mim_id":"300272","title":"HISTONE DEACETYLASE 6; HDAC6","url":"https://www.omim.org/entry/300272"}],"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/HAT1"},"hgnc":{"alias_symbol":["KAT1"],"prev_symbol":[]},"alphafold":{"accession":"O14929","domains":[{"cath_id":"3.90.360.10","chopping":"23-136","consensus_level":"medium","plddt":95.7589,"start":23,"end":136}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14929","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14929-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14929-F1-predicted_aligned_error_v6.png","plddt_mean":92.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HAT1","jax_strain_url":"https://www.jax.org/strain/search?query=HAT1"},"sequence":{"accession":"O14929","fasta_url":"https://rest.uniprot.org/uniprotkb/O14929.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14929/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14929"}},"corpus_meta":[{"pmid":"9427644","id":"PMC_9427644","title":"Nucleosomal DNA regulates the 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The holoenzyme consists of two subunits: the catalytic HAT1 subunit and p46, which binds core histones and greatly stimulates HAT1 acetyltransferase activity. Both p46 and the related p48 (CAF-1 small subunit) bind directly to helix 1 of histone H4, a region inaccessible in chromatin.\",\n      \"method\": \"Purification from human 293 cells, in vitro acetyltransferase assay on soluble vs. nucleosomal substrates, specific antibodies, direct binding assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, substrate specificity assay, direct binding assays, multiple orthogonal methods\",\n      \"pmids\": [\"9427644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Crystal structure of yeast Hat1 in complex with acetyl-CoA solved at 2.3 Å resolution. Hat1 has an elongated curved structure with AcCoA bound in a cleft on the concave surface marking the active site, and a channel across the protein that is the likely histone substrate binding site. This structure established Hat1 as the founding paradigm for the GCN5-related N-acetyltransferase (GNAT) superfamily.\",\n      \"method\": \"X-ray crystallography at 2.3 Å resolution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with bound cofactor, functionally validated active site, replicated structural model used by many subsequent studies\",\n      \"pmids\": [\"9727486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast HAT1 and HAT2 are both required for two acetyltransferase activities: the cytoplasmic type B enzyme and a nuclear free-histone H4-specific acetyltransferase. Both complexes share the same 42 kDa HAT1 catalytic subunit but differ in molecular mass (cytoplasmic ~150 kDa; nuclear ~110 kDa), establishing HAT1 as a component of both cytoplasmic and nuclear acetyltransferase complexes.\",\n      \"method\": \"Genetic analysis using hat1, hat2, and gcn5 single and double yeast mutants; biochemical fractionation and activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistatic genetic analysis combined with biochemical fractionation and activity assays, replicated across multiple mutant strains\",\n      \"pmids\": [\"9575221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The Xenopus Hat1 holoenzyme contains three components: the catalytic Hat1 subunit, RbAp48 (a phosphoprotein), and 14-3-3 proteins (which bind RbAp48 via its consensus phosphoserine recognition motif). The holoenzyme specifically acetylates free but not nucleosomal histone H4 and is localized in the oocyte nucleus where acetylated histones are stored. After oocyte maturation, Hat1 redistributes to the cytoplasm.\",\n      \"method\": \"Purification from Xenopus oocytes, biochemical fractionation, in vitro acetyltransferase assay, localization by cell fractionation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — purification of native complex, multiple components identified, in vitro activity assay, localization by fractionation, single lab\",\n      \"pmids\": [\"10529179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HAT1 substrate specificity requires positively charged residues (Lys or Arg) at positions 8 and 16 of the H4 N-terminal tail; replacing Lys-8 and Lys-16 with glutamines abolishes acetylation. Phosphorylation of Ser-1 of H4 depresses acetylation by both yeast Hat1p and human HAT-B. Lys-12 of H4 is preferentially acetylated by human HAT-B. Prior acetylation of Lys-8 and Lys-16 of H4 prevents Hat1 from acetylating Lys-5 and Lys-12, demonstrating that pre-existing H4 acetylation regulates Hat1 activity.\",\n      \"method\": \"In vitro HAT assays using synthetic H4 N-terminal peptides with specific mutations and chemical modifications; yeast Hat1p and human HAT-B complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined synthetic substrates, multiple mutants tested, site-specific mechanistic conclusions supported by biochemical data\",\n      \"pmids\": [\"11585814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hat1 H4 tail interaction requires positively charged amino acids at positions 8 and 16 of H4; Lys-12 is preferentially acetylated by human HAT-B. Deletion of hat1 from fission yeast S. pombe causes increased sensitivity to the DNA-damaging agent MMS even without additional H3 tail mutations, demonstrating an evolutionarily conserved role for Hat1 in DNA damage repair.\",\n      \"method\": \"In vitro HAT assays on synthetic H4 peptides; genetic analysis in S. pombe hat1Δ strains with MMS sensitivity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — combined in vitro enzymatic analysis and genetic epistasis across two yeast species\",\n      \"pmids\": [\"17052979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In S. pombe, Hat1 (Kat1) is associated with the RbAp46 homologue Mis16 (an essential protein). The Hat1 complex acetylates H4 Lys5 and Lys12. Deletion of hat1 alone (without additional H3 tail mutations) is sufficient to cause loss of silencing specifically at telomeres, and is accompanied by increased H4 acetylation in subtelomeric chromatin, establishing a direct link between Hat1, H4 acetylation, and repressed telomeric chromatin.\",\n      \"method\": \"Co-immunoprecipitation (Hat1-Mis16 interaction), in vitro acetyltransferase assay, genetic deletion of hat1, silencing assays at telomeres/centromeres/mating-type locus in S. pombe\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, in vitro activity assay, clean genetic KO with defined chromatin and silencing phenotype\",\n      \"pmids\": [\"22771823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAT1 acetylates the transcriptional repressor PLZF upon activation by CaMK2 signaling downstream of Toll-like receptor or TNF-α receptor stimulation. Acetylated PLZF assembles a repressor complex containing HDAC3 and NF-κB p50 that limits the NF-κB transcriptional response. Mutation of key residues in PLZF and HAT1, or reduction of CaMK2 activity, curtails control of inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of key acetylation residues in PLZF and HAT1, kinase activity assays, cytokine measurement, genetic knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis with functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25865065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human HAT1 acetylates lysine 5 of histone H2A in vivo, in addition to H4 K5 and K12. Knockdown of HAT1 in HeLa cells (with abrogated Tip60 activity) reduces acetylation of H4-K5, H4-K12, and H2A-K5 in cytosolic and nuclear/insoluble nuclear protein fractions, and impairs colony-forming efficiency.\",\n      \"method\": \"shRNAmir-mediated knockdown of HAT1 in HeLa cells expressing catalytically dead Tip60, Western blotting of histone fractions\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific knockdown with competing enzyme disabled, multiple histone substrate sites assessed by Western blot in multiple fractions\",\n      \"pmids\": [\"24682716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Candida albicans, Hat1 (catalytic subunit of the NuB4 complex) is required for efficient repair of both exogenous and endogenous DNA damage, and its loss causes accumulation of DNA damage and a switch from yeast-like to pseudohyphal growth. Reduction of histone H4 levels phenocopies Hat1 loss, suggesting that insufficient H4 supply for chromatin deposition is the key functional consequence of Hat1 deficiency.\",\n      \"method\": \"Conditional Hat1 depletion, DNA damage assays (sensitivity to MMS, H2O2), morphological analysis, histone H4 reduction experiments\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple defined phenotypic readouts and genetic epistasis with H4 levels, single lab\",\n      \"pmids\": [\"23075292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In Drosophila, Hat1 forms a novel complex with the histone chaperone Caf1/Rbap48 and CENP-A/H4. Hat1 is required for proper CENP-A loading into chromatin, as Hat1 knockdown in S2 cells reduces incorporation of newly synthesized CENP-A. CENP-A/Cid interacts with the Hat1 complex via an N-terminal region that is acetylated in cytoplasmic but not nuclear CENP-A, suggesting a HAT activity-independent escort function for Hat1.\",\n      \"method\": \"Co-immunoprecipitation to define complex, RNAi knockdown in S2 cells with CENP-A loading assay, acetylation site mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP defining new complex, RNAi knockdown with functional centromere loading readout, single lab\",\n      \"pmids\": [\"26586808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK directly phosphorylates HAT1, resulting in its activation. AMPK-mediated HAT1 activation promotes a more relaxed chromatin structure favoring transcription of nuclear genes involved in mitochondrial biogenesis (e.g., PGC-1α, Tfam, UCP2/3). These effects were observed in human umbilical vein cells treated with pharmacological AMPK activators or pulsatile shear stress, and in aortas of mice given AMPK activators (requiring AMPK2α).\",\n      \"method\": \"Identification of AMPK consensus phosphorylation sequences in HAT1; phosphorylation assays; nucleosome remodeling and gene expression assays in endothelial cells and mouse aortas; pharmacological AMPK activation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro phosphorylation assay combined with cellular and in vivo functional readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28143904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HAT1 binds specifically to promoters of histone H4 genes (in addition to its canonical cytoplasmic acetyltransferase role), and HAT1-dependent transcription of H4 genes requires an acetate-sensitive promoter element. HAT1 is critical for S-phase progression and maintenance of H3K9 acetylation at proliferation-associated genes including histone genes, establishing a feedforward circuit where HAT1 captures acetyl groups on nascent histones and drives H4 production.\",\n      \"method\": \"ChIP-seq (HAT1 complex at H4 gene promoters), S-phase progression assays, H3K9ac ChIP, metabolic acetate perturbation, genetic knockdown/overexpression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, functional S-phase assays, acetate-sensitive promoter element validated, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"31278053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of HAT1 in conditional mouse knockout leads to early-onset aging phenotypes and mitochondrial defects. Hat1-/- MEFs exhibit mitochondrial dysfunction; Hat1+/- MEFs show elevated ROS and early senescence with high p21 levels. Hat1 protein localizes to mitochondria, suggesting a direct role in acetylation of mitochondrial proteins.\",\n      \"method\": \"Conditional mouse knockout, MEF isolation, ROS assays, senescence assays (p21, β-galactosidase), mitochondrial function assays, subcellular fractionation (mitochondrial localization)\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO model, multiple orthogonal cellular phenotypic readouts, direct localization by fractionation, replicated across Hat1+/- and Hat1-/- cells\",\n      \"pmids\": [\"31290578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HAT1 promotes assembly and epigenetic regulation of HBV cccDNA minichromosome. HAT1 depletion reduces HBV replication and cccDNA accumulation, impairs histone H3/H4 assembly and deposition of HBx and p300 onto cccDNA. HAT1 modifies acetylation of H3K27, H4K5, and H4K12 on cccDNA minichromosome. lncRNA HULC scaffolds a HAT1/HULC/HBc complex responsible for cccDNA modification. HBV activates HAT1 through HBx-co-activated Sp1 in a positive feedback manner.\",\n      \"method\": \"HAT1 knockdown, cccDNA-ChIP, confocal assays, RIP assays, RNA pulldown, Southern blot in liver-chimeric mouse model and hepatocyte cell lines\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, RIP, pulldown) in a complex model system, single lab\",\n      \"pmids\": [\"31695772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, Hat1 is the main acetyltransferase responsible for H4-K5 and H4-K12 acetylation in embryos. However, loss of Hat1 (and H4-K5/K12 acetylation) does not impair nuclear transport of histone H4, indicating these marks are not required for H4 nuclear import. Loss of Hat1 causes dysregulation of over 2000 genes, implying a broad role in developmental transcriptional programs.\",\n      \"method\": \"Hat1 loss-of-function mutant generation in Drosophila, Western blotting for H4K5ac/H4K12ac, nuclear localization assay for H4 (including K5R/K12R double point mutants), RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with multiple orthogonal readouts (protein acetylation, localization, transcriptomics), single lab\",\n      \"pmids\": [\"31784689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Proteomics of Hat1+/+ vs Hat1-/- mouse embryonic fibroblasts identified 65 proteins with ≥2.5-fold decreased acetylation in Hat1-/- cells. The most affected was the autoregulatory loop of CBP (CREB-binding protein), which decreased up to 20-fold. Hat1-dependent acetylation was found on transcriptional regulators (p53), chromatin structural proteins, and mitochondrial proteins. Hat1 mitochondrial localization (by fractionation) supports a direct role in mitochondrial protein acetylation.\",\n      \"method\": \"Unbiased proteomics (label-free quantitation), acetyllysine affinity purification/MS, Hat1+/+ vs Hat1-/- MEFs, subcellular fractionation\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomics with affinity enrichment, genetic KO comparison, multiple substrate identifications, mitochondrial localization confirmed by fractionation\",\n      \"pmids\": [\"32081014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HAT1 acts as a methacryltransferase, catalyzing a newly discovered histone post-translational modification, lysine methacrylation (Kmea). Biochemical studies show that HAT1 writes histone Kmea marks and SIRT2 acts as the corresponding de-methacrylase. 27 Kmea-modified histone sites were identified in HeLa cells.\",\n      \"method\": \"Affinity enrichment with pan-Kmea antibody, mass spectrometry, in vitro enzymatic assays with HAT1 and SIRT2, antibody validation with chemical approaches\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay establishing writer/eraser, MS identification of sites, antibody validation with chemical methods, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34961760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of HAT1 results in loss of accessibility of large megabase-scale heterochromatin domains (HAT1-dependent Accessibility Domains, HADs) comprising ~10% of the mouse genome. HAT1 globally represses H3K9me3 levels, and HADs correspond to regions with HAT1-dependent increases in H3K9me3 peak density. HADs overlap with a subset of Lamin-Associated Domains (LADs), and HAT1 is required to maintain nuclear structure and integrity.\",\n      \"method\": \"ATAC-seq (chromatin accessibility), H3K9me3 ChIP-seq, HAT1 knockout MEFs, LAD mapping, nuclear structure imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genome-wide orthogonal assays (ATAC-seq, ChIP-seq), clean KO model, mechanistic link between HAT1 and heterochromatin/LAD structure established\",\n      \"pmids\": [\"34788845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HAT1 directly promotes acetylation of the non-histone substrate ACSL4 at lysine 383, enhancing ACSL4 protein stability by inhibiting F-box protein FBXO10-mediated K48-linked ubiquitination. SIRT3 mediates deacetylation of ACSL4, while HDAC2 enhances ACSL4 acetylation indirectly by inhibiting SIRT3 transcription.\",\n      \"method\": \"Co-immunoprecipitation (HAT1-ACSL4 interaction), in vitro acetylation assay, site-directed mutagenesis (K383), ubiquitination assay, in vitro deacetylation assay with SIRT3\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro acetylation and deacetylation assays, mutagenesis of target site, ubiquitination assay, single lab\",\n      \"pmids\": [\"40050614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HAT1 directly acetylates HIF2A at K512 and K596, stabilizing HIF2A under both normoxia and hypoxia. Acetylation-mimic mutations (K512Q or K596Q) restore HIF2A stability in HAT1-silenced cells. HAT1 and HIF2A interact with each other and co-occupy the VEGFA promoter. The HAT1-HIF2A axis is essential for hypoxia-promoted cancer stem cell maintenance.\",\n      \"method\": \"Co-immunoprecipitation (HAT1-HIF2A), site-directed mutagenesis of acetylation sites (K512, K596), HAT1 silencing with HIF2A stability assays, ChIP (HAT1 and HIF2A at VEGFA promoter), cancer stem cell assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, mutagenesis of target sites, ChIP validation, functional stem cell assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36410688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The crystal structure of the Hat1-Hat2 acetyltransferase complex bound to Asf1-H3-H4 reveals that the core domains of both H3 and H4 interact with Hat1 and Hat2, and the N-terminal tail of H3 makes extensive contact with Hat2. This expands the known histone-protein interaction landscape and implicates Hat2/RbAp46/48 in passing histones between chaperones.\",\n      \"method\": \"Cryo-EM/X-ray crystallography of the Hat1-Hat2-Asf1-H3-H4 complex\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of multi-component complex with full-length histones, detailed interaction map, single lab but rigorous structural data\",\n      \"pmids\": [\"35393344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The FOXP3/HAT1 axis controls CCR4 expression in Tregs via epigenetic regulation of the CCR4 promoter. FOXP3 recruits HAT1 to the CCR4 promoter, and this complex mediates permissive (H3K23ac, H3K27ac) or repressive (H3K14ac, H3K18ac) acetylation of histone H3 to regulate CCR4 gene expression in Tregs.\",\n      \"method\": \"Co-immunoprecipitation (FOXP3-HAT1), ChIP at CCR4 promoter for FOXP3 and histone acetylation marks, overexpression and knockdown in Treg models, murine tumor models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP establishing promoter complex and histone marks, in vivo tumor model validation, single lab\",\n      \"pmids\": [\"35222362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human HAT1 has two isoforms: isoform a (418 aa) localized exclusively in the nuclear matrix, and isoform b (334 aa) found in cytoplasm, nucleoplasm, chromatin, and nuclear matrix of normal human keratinocytes. Cells undergoing mitosis have elevated nuclear Hat1. Exposure to heavy-ion particles or H2O2 triggers increased nuclear Hat1 staining regulated by PI3K and MAPK signaling pathways.\",\n      \"method\": \"Immunohistochemistry, subcellular fractionation, immunofluorescence microscopy in normal human keratinocytes; pharmacological inhibition of PI3K and MAPK\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation and immunostaining in multiple cell states, pathway involvement by pharmacological inhibition, single lab\",\n      \"pmids\": [\"20148353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HAT1 activates YTHDF2 transcription through histone acetylation of the YTHDF2 promoter in retinal cells. YTHDF2 in turn triggers m6A-dependent instability and degradation of ITGB1 mRNA. The resulting suppression of ITGB1 inhibits the FAK/PI3K/AKT signaling pathway in retinal Müller cells and endothelial cells.\",\n      \"method\": \"HAT1 overexpression/knockdown, ChIP (histone acetylation at YTHDF2 promoter), mRNA stability assays, pathway (FAK/PI3K/AKT) analysis by Western blotting, in vivo STZ-induced DR mouse model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating promoter acetylation, mRNA stability assays, in vivo validation, single lab\",\n      \"pmids\": [\"34098071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In rice, HAT1 (HAG704) acetylates histone H4K5 and H4K16, and H4K5 acetylation activity requires the ACL subunit A2 (ACLA2). ACL and HAT1 form a nuclear module; ACLA2 is present in nuclear condensates and is required for nuclear acetyl-CoA accumulation. Loss of either ACLA2 or HAT1 impairs cell division in developing endosperm, reduces H4K5ac at overlapping genomic regions, and causes S-phase stagnation.\",\n      \"method\": \"Co-IP (ACLA2-HAT1 interaction), in vitro acetyltransferase assay (H4K5, H4K16), H4K5ac ChIP-seq, cell cycle analysis, genetic mutations in rice endosperm\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro enzymatic assay, ChIP-seq, cell cycle phenotype, single lab with multiple orthogonal methods (rice ortholog)\",\n      \"pmids\": [\"37277331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear ACLY recruits and physically interacts with HAT1 (and P300) in oocytes and early embryos, supplying acetyl-CoA for histone acetylation to activate transcription required for embryogenesis. AKT-mediated phosphorylation of ACLY at Thr447/Ser451/Ser455 drives its nuclear translocation and facilitates its interaction with HAT1 and P300.\",\n      \"method\": \"Co-IP (ACLY-HAT1 interaction), maternal knockout, zygotic KO, histone acetylation assays, subcellular fractionation, AKT inhibitor studies\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing physical interaction, multiple genetic models, functional histone acetylation readout, single lab\",\n      \"pmids\": [\"40470746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HAT1 is a component of a novel RIP1/3-SIRT1/2-HAT1/4 complex identified by mass spectrometry and co-immunoprecipitation. Mass spectrometry identified five acetylation sites in the kinase and death domain of RIP1, and a pan-SIRT inhibitor increases RIP1 acetylation, with acetylation of the RIP1 death domain modulating cell death.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry (complex identification and acetylation site mapping), mutagenesis of acetylated lysines in RIP1, enzymatic assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — complex identified by MS and co-IP, mechanistic link of HAT1 specifically (vs HAT4 or SIRTs) within the complex is not separately established\",\n      \"pmids\": [\"29535128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMGB1 physically interacts with SET and HAT1 in lung adenocarcinoma cells to form a HMGB1/SET/HAT1 complex that inhibits H3K9 and H3K27 acetylation, represses SASH1 expression, and thereby promotes glycolysis and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (HMGB1, SET, HAT1), H3K9ac/H3K27ac Western blotting, SASH1 ChIP assays, functional glycolysis and invasion assays, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing complex, ChIP for histone marks at SASH1 promoter, in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"37794134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans embryos, HAT-1 (with RbAp46/48LIN-53) is required for chromatinization and de novo centromere (CENP-AHCP-3) formation on artificial chromosomes. Depletion of HAT-1 causes loss of both CENP-AHCP-3 and Mis18BP1KNL-2 initial deposition at de novo centromeres on artificial chromosomes, distinguishing this from centromere maintenance on endogenous chromosomes.\",\n      \"method\": \"RNAi depletion of HAT-1 and LIN-53 in C. elegans embryos, immunofluorescence for CENP-A, Mis18BP1, H3K9ac/H4K5ac/H4K12ac, artificial chromosome segregation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi in defined developmental context, multiple centromere component readouts, functional segregation assay, single lab\",\n      \"pmids\": [\"33872374\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HAT1 (KAT1) is a type B histone acetyltransferase that forms a nuclear/cytoplasmic complex with RbAp46/48 (and in some contexts 14-3-3 proteins) to acetylate newly synthesized histone H4 at Lys5 and Lys12 (and H2A at Lys5), a modification that is required for replication-coupled chromatin assembly, epigenetic inheritance of heterochromatin (including LAD-associated domains and telomeric silencing), DNA damage repair, CENP-A loading, S-phase progression, and H4 gene transcription via promoter binding; beyond histones, HAT1 also catalyzes lysine methacrylation and acetylates non-histone substrates including PLZF (modulating NF-κB signaling), HIF2A (stabilizing hypoxic response), and ACSL4 (enhancing ferroptosis sensitivity), and its activity is regulated by AMPK-mediated phosphorylation and by interaction with metabolic enzymes (ACL/ACLY) that supply local acetyl-CoA.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HAT1 is the catalytic subunit of the type B histone acetyltransferase that acetylates newly synthesized, soluble (non-nucleosomal) histone H4 at Lys5 and Lys12 and H2A at Lys5, the committed step that primes nascent histones for replication-coupled chromatin assembly [#0, #8]. It functions as a holoenzyme with the histone-binding chaperone subunit RbAp46/48 (yeast Hat2, S. pombe Mis16), which binds helix 1 of H4 and core histones to greatly stimulate catalysis, and in some contexts associates with 14-3-3 proteins via phosphorylated RbAp48 [#0, #3, #6]; structural work defined Hat1 as the founding member of the GNAT superfamily and mapped how the Hat1-RbAp46/48 module engages H3-H4 handed off from the chaperone Asf1 [#1, #21]. Substrate selection is governed by the H4 tail: acetylation requires positively charged residues at H4 positions 8 and 16, is blocked by Ser1 phosphorylation, and is precluded by prior acetylation of Lys8/Lys16, so existing modifications gate HAT1 activity [#4]. Through this histone-deposition activity HAT1 supports diverse genome functions — epigenetic maintenance of repressed telomeric and large heterochromatin/LAD-associated domains, global restraint of H3K9me3, de novo and replication-coupled CENP-A loading at centromeres, DNA damage repair, and S-phase progression coupled to a feedforward circuit in which HAT1 binds H4 gene promoters to drive histone production [#6, #18, #10, #29, #5, #12]. HAT1 activity is integrated with metabolism and signaling: AMPK directly phosphorylates and activates it, and it partners with nuclear acetyl-CoA-generating enzymes (ACL/ACLY) to obtain local cofactor for histone acetylation during transcriptional activation and development [#11, #25, #26]. Beyond histones HAT1 acetylates non-histone substrates including PLZF to assemble an HDAC3/NF-\\u03baB p50 repressor that limits inflammatory signaling, HIF2A (K512/K596) to stabilize the hypoxic response, and ACSL4 (K383) to block its ubiquitin-mediated degradation, and it writes a distinct histone mark, lysine methacrylation, opposed by SIRT2 [#7, #20, #19, #17]. Loss of HAT1 in mice produces mitochondrial dysfunction, elevated ROS, and early senescence/aging phenotypes, consistent with its localization to mitochondria and a broad non-histone acetylome including CBP and p53 [#13, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the core enzymatic identity of HAT1 as a type B HAT that modifies free histones, defining its substrate sites and its dependence on an accessory histone-binding subunit.\",\n      \"evidence\": \"Purification of the human holoenzyme from 293 cells with in vitro acetyltransferase assays on soluble vs. nucleosomal substrates and direct binding assays; crystal structure of yeast Hat1-acetyl-CoA; genetic analysis of yeast hat1/hat2 mutants\",\n      \"pmids\": [\"9427644\", \"9727486\", \"9575221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how the cytoplasmic deposition product is transferred to chromatin\", \"Mechanism distinguishing cytoplasmic from nuclear complex forms unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the native holoenzyme composition and its regulated subcellular partitioning, linking HAT1 to histone storage pools.\",\n      \"evidence\": \"Purification from Xenopus oocytes identifying Hat1, RbAp48, and 14-3-3; in vitro activity assays and localization by fractionation across oocyte maturation\",\n      \"pmids\": [\"10529179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of 14-3-3 in catalysis or trafficking not defined\", \"Trigger for nuclear-to-cytoplasmic redistribution unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the recognition rules and combinatorial regulation of HAT1 by the H4 tail, showing pre-existing marks gate its activity.\",\n      \"evidence\": \"In vitro HAT assays on synthetic H4 peptides bearing point mutations and chemical modifications, using yeast Hat1p and human HAT-B\",\n      \"pmids\": [\"11585814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Ser1-phosphorylation crosstalk not tested\", \"Did not address selectivity on H2A\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected HAT1 to genome maintenance by showing a conserved requirement in DNA damage repair independent of H3 tail modification.\",\n      \"evidence\": \"In vitro peptide HAT assays plus MMS sensitivity in S. pombe hat1\\u0394 strains; later extended in C. albicans with H4-level epistasis\",\n      \"pmids\": [\"17052979\", \"23075292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repair defect is solely due to deficient H4 supply vs direct repair role unresolved\", \"Specific repair pathway affected not pinpointed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a direct epigenetic role for HAT1 in heterochromatic silencing, linking its H4 acetylation activity to repressed telomeric chromatin.\",\n      \"evidence\": \"Reciprocal Hat1-Mis16 co-IP, in vitro acetyltransferase assays, and silencing assays in S. pombe hat1 deletion strains\",\n      \"pmids\": [\"22771823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an activating acetylation mark promotes silencing mechanistically not explained\", \"Mammalian generality not addressed in this study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended HAT1 substrate range to H2A K5 in vivo and to non-histone targets, opening a non-chromatin signaling function via PLZF.\",\n      \"evidence\": \"shRNA knockdown with histone fraction Westerns (Tip60-disabled HeLa); co-IP, residue mutagenesis, and cytokine readouts for PLZF/CaMK2/NF-\\u03baB\",\n      \"pmids\": [\"24682716\", \"25865065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect H2A-K5 acetylation by HAT1 not fully separated from compensating enzymes\", \"Generality of PLZF axis beyond TLR/TNF stimulation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated HAT1 in centromere identity by showing a role in CENP-A loading, partly via a chaperone-escort function distinct from catalysis.\",\n      \"evidence\": \"Co-IP defining a Hat1-Caf1/Rbap48-CENP-A/H4 complex and RNAi CENP-A loading assays in Drosophila S2 cells; later C. elegans de novo centromere assays\",\n      \"pmids\": [\"26586808\", \"33872374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Separation of catalytic vs escort contributions to CENP-A deposition incomplete\", \"Whether endogenous centromere maintenance requires HAT1 not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified upstream signaling control of HAT1, linking AMPK phosphorylation to HAT1-driven chromatin relaxation and mitochondrial biogenesis gene expression.\",\n      \"evidence\": \"Identification of AMPK consensus sites, phosphorylation and nucleosome/gene-expression assays in endothelial cells and mouse aortas with pharmacological AMPK activation\",\n      \"pmids\": [\"28143904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite-specific functional mapping incomplete\", \"Direct enzymatic consequence of phosphorylation on acetyl-transfer kinetics not measured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a feedforward transcriptional circuit and physiological consequence of HAT1 loss, tying nascent-histone acetylation to H4 gene production, S-phase, and organismal aging.\",\n      \"evidence\": \"ChIP-seq of HAT1 at H4 promoters with acetate-sensitive element analysis and S-phase assays; conditional mouse KO with ROS, senescence, and mitochondrial assays; Drosophila LOF transcriptomics\",\n      \"pmids\": [\"31278053\", \"31290578\", \"31784689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H4-K5/K12 marks themselves are dispensable for H4 import (per Drosophila) vs required for downstream assembly not reconciled\", \"Mechanism linking mitochondrial localization to acetylation targets not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the HAT1-dependent acetylome, revealing broad non-histone substrates including CBP and p53 and supporting a direct mitochondrial role.\",\n      \"evidence\": \"Label-free quantitative proteomics with acetyllysine affinity-MS comparing Hat1+/+ and Hat1-/- MEFs plus subcellular fractionation\",\n      \"pmids\": [\"32081014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect acetylation of identified targets not validated site by site\", \"Functional consequences of mitochondrial protein acetylation undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed genome-scale chromatin architecture functions and an unexpected enzymatic capability for HAT1.\",\n      \"evidence\": \"ATAC-seq and H3K9me3 ChIP-seq in HAT1-KO MEFs with LAD mapping and nuclear imaging; pan-Kmea MS and in vitro writer/eraser assays with HAT1/SIRT2\",\n      \"pmids\": [\"34788845\", \"34961760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HAT1 represses H3K9me3 globally (direct vs indirect) not mechanistically resolved\", \"Physiological role of histone methacrylation undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Consolidated structural understanding of histone hand-off and broadened the non-histone substrate set to stress and metabolic regulators.\",\n      \"evidence\": \"Structure of Hat1-Hat2-Asf1-H3-H4; co-IP/mutagenesis/ChIP defining HIF2A (K512/K596) stabilization and ACSL4 (K383) stabilization, and FOXP3-recruited promoter acetylation\",\n      \"pmids\": [\"35393344\", \"36410688\", \"40050614\", \"35222362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo stoichiometry of non-histone acetylation events unclear\", \"Context determinants directing HAT1 to histone vs non-histone substrates unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established metabolic coupling of HAT1 to local acetyl-CoA supply via ACL/ACLY, integrating nutrient state with histone acetylation and cell division.\",\n      \"evidence\": \"Co-IP, in vitro HAT assays, and H4K5ac ChIP-seq linking HAT1 to ACLA2 in rice endosperm; ACLY-HAT1 interaction in oocytes/embryos with AKT-driven nuclear translocation\",\n      \"pmids\": [\"37277331\", \"40470746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of channeled acetyl-CoA to HAT1 active site lacking\", \"Conservation of ACLY-HAT1 module in somatic mammalian cells not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HAT1's many reported non-histone substrates and disease-associated complexes are mechanistically prioritized in vivo, and how its mitochondrial functions relate to its canonical histone-deposition role, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating cytoplasmic deposition, nuclear transcriptional, and mitochondrial roles\", \"Substrate-selection determinants between histone and non-histone targets unknown\", \"No human Mendelian disease link established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 7, 19, 20]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [13, 16]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [12, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 10, 29]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 22]}\n    ],\n    \"complexes\": [\n      \"HAT1-RbAp46/48 (type B HAT-B) holoenzyme\",\n      \"NuB4 complex\",\n      \"Hat1-RbAp48-14-3-3 holoenzyme\",\n      \"HMGB1/SET/HAT1 complex\"\n    ],\n    \"partners\": [\n      \"RBBP7\",\n      \"RBBP4\",\n      \"ACLY\",\n      \"HIF2A\",\n      \"ACSL4\",\n      \"PLZF\",\n      \"FOXP3\",\n      \"CENPA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}