{"gene":"HAT1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"Human HAT1 holoenzyme purified from 293 cells consists of two subunits: a catalytic subunit (HAT1) and a core-histone-binding subunit (p46); p46 greatly stimulates HAT1 acetyltransferase activity. The holoenzyme acetylates soluble (but not nucleosomal) histone H4 at Lys5 and Lys12, and histone H2A at Lys5. Both p46 and p48 bind directly to helix 1 of histone H4.","method":"Affinity purification of holoenzyme from human 293 cells, in vitro acetyltransferase assays on soluble vs. nucleosomal substrates, direct binding assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 — reconstituted holoenzyme, in vitro assay with defined substrates, direct binding experiments, multiple orthogonal methods","pmids":["9427644"],"is_preprint":false},{"year":1998,"finding":"Crystal structure of yeast Hat1 in complex with acetyl-CoA at 2.3 Å resolution revealed an elongated curved structure with AcCoA bound in a cleft on the concave surface marking the active site; a channel across the protein is the probable histone substrate binding site. The structure established Hat1 as the founding member of the GCN5-related N-acetyltransferase (GNAT) superfamily.","method":"X-ray crystallography of Hat1–AcCoA complex at 2.3 Å resolution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional interpretation, foundational structural paper","pmids":["9727486"],"is_preprint":false},{"year":1998,"finding":"Yeast HAT1 and HAT2 together constitute both the cytoplasmic type B histone acetyltransferase and a nuclear free-histone-H4-specific acetyltransferase. The catalytic subunit of both complexes is the 42 kDa HAT1 protein; the cytoplasmic complex is ~150 kDa and the nuclear complex is ~110 kDa.","method":"Biochemical fractionation of extracts from hat1, hat2, and gcn5 single and double mutant yeast strains; in vitro HAT assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — genetic mutant panel combined with biochemical fractionation and in vitro activity assays","pmids":["9575221"],"is_preprint":false},{"year":1999,"finding":"Xenopus Hat1 holoenzyme purified from oocyte nuclei contains the catalytic subunit Hat1, the retinoblastoma-associated protein RbAp48, and 14-3-3 proteins. The holoenzyme specifically acetylates free histone H4 but not nucleosomal histones. The holoenzyme is stored in vast excess in the oocyte nucleus where acetylated histones are stockpiled; following oocyte maturation it redistributes to the cytoplasm.","method":"Biochemical purification from Xenopus oocytes, in vitro acetyltransferase assays, subcellular fractionation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — purified complex, in vitro assay, fractionation with functional context","pmids":["10529179"],"is_preprint":false},{"year":2001,"finding":"Acetylation of histone H4 at Lys8 and Lys16 by other acetyltransferases strongly inhibits subsequent acetylation by Hat1 at Lys5 and Lys12; pre-treatment with histone deacetylase restores Hat1 activity. Additionally, Hat1 requires positively charged amino acids (K or R) at H4 positions 8 and 16 for efficient catalysis, and phosphorylation of H4 Ser1 depresses Hat1 activity.","method":"In vitro HAT assays using synthetic H4 N-terminal peptides with defined modifications; yeast Hat1p and human HAT-B complex tested","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted assay with defined peptide substrates and multiple modifications tested","pmids":["11585814"],"is_preprint":false},{"year":2006,"finding":"Hat1 preferentially acetylates Lys12 of histone H4 over Lys5 in vitro, consistent with the structural model of H4 tail binding. Deletion of hat1 in Schizosaccharomyces pombe causes increased sensitivity to the DNA-damaging agent methyl methanesulfonate even without additional histone H3 mutations, demonstrating a Hat1-dependent role in DNA damage repair that is evolutionarily conserved.","method":"In vitro HAT assays on H4 peptides; yeast genetic deletion and MMS sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro assay combined with genetic loss-of-function and defined phenotypic readout","pmids":["17052979"],"is_preprint":false},{"year":2014,"finding":"Human Hat1 acetylates lysine 5 of histone H2A in vivo (in addition to H4 K5 and K12). shRNA knockdown of HAT1 in HeLa cells decreased H4K5ac, H4K12ac, and H2AK5ac levels in cytosolic and insoluble nuclear protein fractions.","method":"shRNA knockdown in HeLa cells, quantification of acetylation by Western blot of histone fractions","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined modification readout, single lab","pmids":["24682716"],"is_preprint":false},{"year":2015,"finding":"HAT1 is activated by CaMK2 signalling downstream of Toll-like or TNF-α receptor stimulation. Activated HAT1 then acetylates the transcriptional regulator PLZF, promoting assembly of a repressor complex (PLZF–HDAC3–NF-κB p50) that limits NF-κB-driven inflammatory cytokine production.","method":"Co-immunoprecipitation, mutagenesis of acetylation/phosphorylation sites, kinase activity assays, cytokine measurement upon KD/OE","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis of functional residues, and defined functional readout; single lab","pmids":["25865065"],"is_preprint":false},{"year":2015,"finding":"HAT1 is part of a novel CENP-A preloading complex in Drosophila that also contains Caf1/Rbap48 and CENP-A/H4. Hat1 knockdown in S2 cells reduces incorporation of newly synthesized CENP-A into chromatin. CENP-A interacts with the Hat1 complex via its N-terminal region, which is acetylated in cytoplasmic but not nuclear CENP-A; Hat1 acetyltransferase activity is not responsible for CENP-A acetylation, suggesting a chaperone-like escort function for Hat1.","method":"Co-immunoprecipitation of Hat1 complex, RNAi knockdown with CENP-A loading readout, acetylation mapping","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and RNAi with specific phenotypic readout; single lab","pmids":["26586808"],"is_preprint":false},{"year":2017,"finding":"AMPK directly phosphorylates HAT1, resulting in activation of HAT1 acetyltransferase activity. AMPK-mediated HAT1 activation promotes nucleosome remodeling and expression of mitochondrial biogenesis genes (PGC-1α, Tfam, UCP2/3) in endothelial cells and mouse aorta.","method":"In vitro AMPK phosphorylation assays, pharmacological AMPK activation in HUVECs and in vivo in mice, gene expression analysis","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro kinase assay plus cell and in vivo functional validation; single lab","pmids":["28143904"],"is_preprint":false},{"year":2019,"finding":"HAT1 binds at promoters of histone H4 genes and is required for their transcription via an acetate-sensitive promoter element. HAT1 expression is required for S-phase progression and maintenance of H3K9 acetylation at proliferation-associated loci. These data reveal a feedforward circuit in which HAT1 drives both H4 gene transcription and acetylation of nascent histones.","method":"ChIP-seq, RNA-seq, loss-of-function experiments, S-phase progression assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genome-wide methods combined with functional cell biology readouts","pmids":["31278053"],"is_preprint":false},{"year":2019,"finding":"Conditional knockout of Hat1 in mice causes early-onset aging phenotypes (lordokyphosis, muscle atrophy, cancer, paralysis), early cellular senescence, accumulation of p21, elevated reactive oxygen species, and mitochondrial defects in MEFs, indicating that Hat1 is required for normal mitochondrial function and genome stability in mammals.","method":"Conditional mouse knockout, MEF senescence assays, ROS measurement, mitochondrial function assays","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo KO with multiple orthogonal phenotypic readouts","pmids":["31290578"],"is_preprint":false},{"year":2019,"finding":"Loss of Hat1 in Drosophila results in near-complete loss of histone H4 K5 and K12 acetylation in embryos, identifying Hat1 as the primary H4K5 and H4K12 acetyltransferase at this developmental stage. H4K5/K12 acetylation is not required for nuclear transport of histone H4.","method":"Drosophila Hat1 loss-of-function mutant generation, Western blot of H4 acetylation marks, localization of histone H4 variant, RNA-seq","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — genetic KO in model organism with direct biochemical readout of enzymatic activity","pmids":["31784689"],"is_preprint":false},{"year":2021,"finding":"Loss of HAT1, which acetylates H4K5 and H4K12 during replication-coupled chromatin assembly, results in loss of chromatin accessibility in megabase-scale HAT1-dependent Accessibility Domains (HADs) that overlap with Lamin-Associated Domains. HAT1 globally represses H3K9me3 levels; HADs correspond to regions with HAT1-dependent increases in H3K9me3 peak density. HAT1 is required to maintain nuclear structure and integrity.","method":"HAT1 knockout MEFs, ATAC-seq, ChIP-seq for H3K9me3, nuclear integrity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple orthogonal genome-wide assays and structural readouts","pmids":["34788845"],"is_preprint":false},{"year":2021,"finding":"HAT1 functions as a methacryltransferase, catalyzing lysine methacrylation (Kmea) on histones; SIRT2 acts as the corresponding de-methacrylase. 27 Kmea-modified histone sites were identified in HeLa cells by affinity enrichment and mass spectrometry.","method":"In vitro acetyltransferase assay with methacrylyl-CoA, pan-Kmea antibody affinity enrichment, mass spectrometry, SIRT2 de-modification assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution of novel enzymatic activity with orthogonal chemical and immunological validation","pmids":["34961760"],"is_preprint":false},{"year":2022,"finding":"HAT1 directly acetylates HIF2A at K512 and K596, stabilizing HIF2A protein under normoxia and hypoxia. HAT1 and HIF2A interact physically and co-occupy the VEGFA promoter. HAT1-dependent HIF2A acetylation is required for cancer stem cell maintenance and hypoxia response in glioblastoma cells.","method":"Co-immunoprecipitation, ChIP assay, acetylation-mimic mutations in HIF2A, HAT1 silencing with functional readouts","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, site-directed mutagenesis, and KD with defined phenotypic readout; single lab","pmids":["36410688"],"is_preprint":false},{"year":2022,"finding":"HAT1 directly acetylates ACSL4 at K383, enhancing ACSL4 protein stability by inhibiting FBXO10-mediated K48-linked ubiquitination. HDAC2 enhances ACSL4 acetylation indirectly by suppressing SIRT3 transcription. HAT1-mediated ACSL4 acetylation promotes ferroptosis sensitivity and radiosensitivity in nasopharyngeal carcinoma.","method":"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K383R), ubiquitination assay, in vitro and in vivo radiosensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro acetylation, mutagenesis, and ubiquitination assays with functional validation; single lab","pmids":["40050614"],"is_preprint":false},{"year":2022,"finding":"Structure of the Hat1–Hat2 acetyltransferase complex bound to Asf1–H3–H4 shows that core domains of both H3 and H4 contact Hat1 and Hat2, and the H3 N-terminal tail makes extensive interaction with Hat2/RbAp46. This reveals a chaperone-passing mechanism and implicates Hat2/RbAp46/48 in transferring histones between chaperones.","method":"Cryo-EM/X-ray structure of Hat1–Hat2–Asf1–H3–H4 complex","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure with functional interpretation of histone–chaperone interactions","pmids":["35393344"],"is_preprint":false},{"year":2012,"finding":"Fission yeast Hat1 (Kat1) is associated with Mis16 (RbAp46 homologue) and the Hat1 complex acetylates H4K5 and H4K12. Deletion of hat1 in S. pombe alone is sufficient to cause loss of telomeric silencing, accompanied by increased H4 acetylation in subtelomeric chromatin.","method":"Co-immunoprecipitation of Hat1 complex, in vitro HAT assay, hat1 deletion strain, telomeric silencing assay, ChIP","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1–2 — purified complex, in vitro activity assay, genetic KO with defined silencing readout","pmids":["22771823"],"is_preprint":false},{"year":2018,"finding":"HAT1 is found in a complex with RIP1, RIP3, SIRT1/2, and HAT4. Mass spectrometry identified five acetylation sites in the kinase and death domains of RIP1. SIRT inhibitor MC2494 increases RIP1 acetylation; mutagenesis of acetylated lysines in RIP1 reduces RIP1-dependent cell death.","method":"Immunoprecipitation, mass spectrometry identification of RIP1 acetylation sites, mutagenesis, cell death assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified complex and acetylation sites with mutagenesis validation; single lab","pmids":["29535128"],"is_preprint":false},{"year":2020,"finding":"Unbiased proteomics of Hat1+/+ vs Hat1-/- MEFs identified 65 proteins with >2.5-fold decreased acetylation in the absence of Hat1, including the autoregulatory loop of CBP (decreased ~20-fold). Hat1-dependent acetylation targets include transcriptional regulators (p53), chromatin proteins, and mitochondrial proteins. Hat1 was detected in mitochondria by fractionation.","method":"Acetylome mass spectrometry (label-free quantitation), subcellular fractionation, Hat1 KO MEFs grown on glucose vs. galactose","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 1–2 — unbiased quantitative proteomics of KO vs WT, multiple substrates identified with fractionation","pmids":["32081014"],"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) distributed in cytoplasm, nucleoplasm, chromatin, and nuclear matrix. Irradiation with heavy-ion particles triggers enhanced nuclear accumulation of Hat1 regulated by the PI3K and MAPK signaling pathways.","method":"Immunofluorescence, subcellular fractionation, pharmacological inhibition of PI3K/MAPK","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — localization by immunofluorescence/fractionation with partial signaling follow-up; single lab","pmids":["20148353"],"is_preprint":false},{"year":2023,"finding":"HMGB1 physically interacts with SET and HAT1 to form an HMGB1/SET/HAT1 complex that suppresses H3K9 and H3K27 acetylation, thereby repressing SASH1 transcription and promoting glycolysis and metastasis in lung adenocarcinoma.","method":"Co-immunoprecipitation, ChIP assay for H3K9ac and H3K27ac at SASH1 locus, in vitro and in vivo functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and ChIP with defined functional readout; single lab","pmids":["37794134"],"is_preprint":false},{"year":2023,"finding":"ACL subunit A2 (ACLA2) interacts with HAT1 in rice nuclei and is required for nuclear acetyl-CoA accumulation and HAT1-dependent H4K5 acetylation. The HAT1–ACLA2 module promotes cell division in developing endosperm and controls H4K5 acetylation at specific genomic loci.","method":"Co-immunoprecipitation, nuclear acetyl-CoA measurement, ChIP-seq for H4K5ac, loss-of-function mutants with cell-division readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, biochemical assay, genome-wide ChIP, and genetic KO; ortholog context (rice HAT1)","pmids":["37277331"],"is_preprint":false}],"current_model":"HAT1 (histone acetyltransferase 1) is a type B histone acetyltransferase that forms a holoenzyme with RbAp46/48 (Hat2/Mis16) and acetylates newly synthesized histone H4 at K5 and K12 (and H2A at K5) in both cytoplasm and nucleus during replication-coupled chromatin assembly; its crystal structure defines it as the founding GNAT superfamily member, and beyond canonical histone acetylation it also catalyzes lysine methacrylation on histones, acetylates non-histone substrates including PLZF, HIF2A, and ACSL4, is activated by AMPK and CaMK2 phosphorylation, participates in a nuclear complex at histone H4 gene promoters to coordinate histone production with acetylation, is required for CENP-A loading, DNA damage repair, maintenance of heterochromatin/LAD organization, and normal mitochondrial function, with loss of Hat1 in mice causing early-onset aging and mitochondrial defects."},"narrative":{"teleology":[{"year":1998,"claim":"Defining the HAT1 holoenzyme composition and substrate specificity resolved the long-standing question of which enzyme acetylates newly synthesized H4 in the cytoplasm, establishing that the catalytic subunit requires the RbAp46/48 cofactor and acts on soluble H4 K5/K12 and H2A K5 but not nucleosomal histones.","evidence":"Affinity purification from human 293 cells with in vitro acetyltransferase assays on soluble vs. nucleosomal substrates; biochemical fractionation of yeast hat1/hat2 mutants","pmids":["9427644","9575221"],"confidence":"High","gaps":["Mechanism by which p46/p48 stimulates catalysis was not resolved","Whether HAT1 acts on other substrates beyond H4/H2A was unknown"]},{"year":1998,"claim":"The crystal structure of yeast Hat1 with acetyl-CoA revealed the active-site architecture and founded the GNAT superfamily classification, providing the structural framework for understanding substrate recognition.","evidence":"X-ray crystallography of Hat1–AcCoA complex at 2.3 Å","pmids":["9727486"],"confidence":"High","gaps":["Structure lacked the histone substrate, so the catalytic mechanism of H4 tail recognition was inferred","No structure of the holoenzyme with Hat2/RbAp46"]},{"year":2001,"claim":"Demonstration that pre-existing H4 K8/K16 acetylation and S1 phosphorylation inhibit Hat1 activity established that Hat1 specificity depends on the modification state of its substrate, explaining why it targets only newly synthesized histones.","evidence":"In vitro HAT assays with synthetic H4 peptides bearing defined modifications","pmids":["11585814"],"confidence":"High","gaps":["Whether this cross-talk operates in vivo was not shown","The structural basis for inhibition by neighboring marks was unknown"]},{"year":2006,"claim":"Hat1 deletion in fission yeast causing DNA damage sensitivity revealed that Hat1 functions extend beyond simple histone deposition acetylation to include genome maintenance, an observation conserved across species.","evidence":"S. pombe hat1 deletion with MMS sensitivity assay","pmids":["17052979"],"confidence":"High","gaps":["The molecular mechanism linking H4K5/K12 acetylation to DNA repair was not identified","Whether Hat1 acts directly at damage sites was untested"]},{"year":2012,"claim":"Discovery that Hat1 deletion in S. pombe causes loss of telomeric silencing with increased subtelomeric H4 acetylation showed that Hat1 contributes to heterochromatin maintenance, extending its role beyond replication-coupled assembly.","evidence":"S. pombe hat1 deletion, telomeric silencing assay, ChIP for H4 acetylation","pmids":["22771823"],"confidence":"High","gaps":["Whether this reflects direct or indirect effects on heterochromatin factors was unclear","Not tested in mammalian cells at this time"]},{"year":2015,"claim":"Two studies expanded HAT1 function beyond histones: one showed HAT1 acetylates the transcription factor PLZF downstream of CaMK2 to limit NF-κB inflammatory signaling, and another revealed HAT1 participates in a CENP-A preloading complex with a chaperone-like escort function independent of its acetyltransferase activity.","evidence":"Co-IP, mutagenesis of acetylation/phosphorylation sites with cytokine readouts (PLZF); RNAi of Hat1 in Drosophila S2 cells with CENP-A loading assay","pmids":["25865065","26586808"],"confidence":"Medium","gaps":["PLZF acetylation sites and stoichiometry not fully mapped","Chaperone function of Hat1 for CENP-A not reconstituted in vitro","Both findings from single laboratories"]},{"year":2017,"claim":"AMPK-mediated phosphorylation of HAT1 linked metabolic signaling to chromatin remodeling and mitochondrial biogenesis gene expression, establishing HAT1 as a regulated node integrating energy sensing with epigenetic output.","evidence":"In vitro AMPK kinase assay, pharmacological AMPK activation in HUVECs and mouse aorta, gene expression analysis","pmids":["28143904"],"confidence":"Medium","gaps":["The specific phosphorylation site(s) on HAT1 were not all mapped","Whether AMPK-HAT1 axis operates in non-endothelial tissues was untested"]},{"year":2019,"claim":"Three studies collectively established HAT1 as essential for chromatin homeostasis and organismal health: HAT1 occupies H4 gene promoters to create a feedforward loop coupling histone transcription with acetylation; Drosophila Hat1 loss abolishes nearly all H4K5/K12 acetylation; and conditional Hat1 knockout in mice causes early-onset aging, senescence, and mitochondrial dysfunction.","evidence":"ChIP-seq/RNA-seq in mammalian cells; Drosophila Hat1 KO with Western blot; conditional mouse KO with aging, senescence, ROS, and mitochondrial phenotyping","pmids":["31278053","31784689","31290578"],"confidence":"High","gaps":["Mechanism connecting H4K5/K12 acetylation loss to mitochondrial dysfunction not delineated","Whether the aging phenotype is rescued by catalytic-dead Hat1 restoration was not tested","Direct promoter targets of the feedforward loop beyond H4 genes incompletely defined"]},{"year":2020,"claim":"Unbiased acetylome profiling of Hat1 KO MEFs revealed that HAT1 is required for acetylation of dozens of non-histone proteins including CBP, p53, and mitochondrial proteins, and that Hat1 itself localizes to mitochondria, greatly expanding its substrate repertoire.","evidence":"Quantitative acetylome mass spectrometry of Hat1+/+ vs Hat1−/− MEFs, subcellular fractionation","pmids":["32081014"],"confidence":"High","gaps":["Which acetylation events are direct Hat1 catalytic products vs. indirect effects is unresolved","Mitochondrial import mechanism for Hat1 not determined"]},{"year":2021,"claim":"Two discoveries refined HAT1's chromatin and catalytic scope: loss of HAT1 collapses chromatin accessibility at megabase-scale lamin-associated domains with concomitant H3K9me3 gain, and HAT1 was shown to catalyze lysine methacrylation, a novel acyl modification on histones.","evidence":"HAT1 KO MEFs with ATAC-seq and H3K9me3 ChIP-seq; in vitro methacrylation assay with methacrylyl-CoA and MS validation","pmids":["34788845","34961760"],"confidence":"High","gaps":["How HAT1-dependent acetylation prevents H3K9me3 spreading is mechanistically unresolved","Physiological abundance and functional significance of histone methacrylation unknown","Whether methacrylation uses the same active site geometry as acetylation not structurally addressed"]},{"year":2022,"claim":"The cryo-EM/crystal structure of the Hat1–Hat2–Asf1–H3–H4 complex revealed how the histone chaperone Asf1 hands off the H3–H4 dimer to the HAT1 holoenzyme, with RbAp46/Hat2 making extensive contacts with the H3 N-terminal tail, establishing a chaperone-passing mechanism for replication-coupled chromatin assembly.","evidence":"Cryo-EM and X-ray crystallography of the quaternary complex","pmids":["35393344"],"confidence":"High","gaps":["Downstream hand-off from Hat1 complex to CAF-1 not structurally captured","Whether catalysis occurs during or after chaperone transfer not resolved"]},{"year":2022,"claim":"HAT1 was shown to acetylate non-histone targets HIF2A (K512/K596) and ACSL4 (K383), stabilizing these proteins and linking HAT1 to hypoxia-driven transcription and ferroptosis sensitivity in cancer.","evidence":"Co-IP, in vitro acetylation assay, site-directed mutagenesis with stability/ubiquitination readouts in glioblastoma and nasopharyngeal carcinoma cells","pmids":["36410688","40050614"],"confidence":"Medium","gaps":["Both findings from single laboratories; independent confirmation needed","Whether these non-histone substrates are acetylated by HAT1 in normal (non-cancer) physiology unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural and kinetic basis by which HAT1 distinguishes histone from non-histone substrates; how loss of H4K5/K12 acetylation mechanistically leads to mitochondrial dysfunction and accelerated aging; whether HAT1's mitochondrial localization reflects a direct catalytic role inside mitochondria; and what fraction of the broad acetylome changes in Hat1 KO cells represent direct versus indirect targets.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of HAT1 bound to a non-histone substrate","Mitochondrial import mechanism unknown","Direct vs. indirect acetylation targets not systematically distinguished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,4,5,6,12,14,16]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4,17]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,15,16,20]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,10,13,17,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,3,6]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[20]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[10,13]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,4,5,6,10,12,13,14,17]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10,23]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11]}],"complexes":["HAT1–RbAp46/48 (HAT-B holoenzyme)","HAT1–Hat2–Asf1–H3–H4","HMGB1/SET/HAT1"],"partners":["RBBP7","RBBP4","ASF1A","PLZF","HIF2A","ACSL4","HMGB1","SET"],"other_free_text":[]},"mechanistic_narrative":"HAT1 is a type B histone acetyltransferase and founding member of the GNAT superfamily that acetylates newly synthesized, non-nucleosomal histone H4 at Lys5 and Lys12 and histone H2A at Lys5, functioning as a holoenzyme with the RbAp46/48 (Hat2/Mis16) subunit that stimulates catalytic activity and mediates histone chaperone transfer via Asf1 [PMID:9427644, PMID:35393344]. Beyond canonical histone substrates, HAT1 acetylates non-histone proteins including PLZF, HIF2A, and ACSL4 to regulate inflammatory signaling, hypoxia response, and ferroptosis sensitivity, and catalyzes lysine methacrylation on histones [PMID:25865065, PMID:36410688, PMID:40050614, PMID:34961760]. HAT1 occupies histone H4 gene promoters to drive a feedforward circuit coupling histone production with nascent histone acetylation during S phase, and is required for maintenance of chromatin accessibility at lamin-associated domains, repression of H3K9me3, telomeric silencing, DNA damage repair, and CENP-A loading [PMID:31278053, PMID:34788845, PMID:22771823, PMID:17052979, PMID:26586808]. Conditional Hat1 knockout in mice causes early-onset aging, cellular senescence, and mitochondrial dysfunction, consistent with unbiased acetylome analyses revealing broad HAT1-dependent acetylation of mitochondrial and chromatin-regulatory proteins [PMID:31290578, PMID:32081014]."},"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 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27400176","citation_count":16,"is_preprint":false},{"pmid":"35393344","id":"PMC_35393344","title":"Topography of histone H3-H4 interaction with the Hat1-Hat2 acetyltransferase complex.","date":"2022","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/35393344","citation_count":15,"is_preprint":false},{"pmid":"22771823","id":"PMC_22771823","title":"Schizosaccharomyces pombe Hat1 (Kat1) is associated with Mis16 and is required for telomeric silencing.","date":"2012","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/22771823","citation_count":15,"is_preprint":false},{"pmid":"29777939","id":"PMC_29777939","title":"Variation of genes encoding KAT1, AADAT and IDO1 as a potential risk of depression development.","date":"2018","source":"European psychiatry : the journal of the Association of European Psychiatrists","url":"https://pubmed.ncbi.nlm.nih.gov/29777939","citation_count":15,"is_preprint":false},{"pmid":"29960193","id":"PMC_29960193","title":"Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes.","date":"2018","source":"Pharmacological reports : PR","url":"https://pubmed.ncbi.nlm.nih.gov/29960193","citation_count":15,"is_preprint":false},{"pmid":"20148353","id":"PMC_20148353","title":"Irradiation with heavy-ion particles changes the cellular distribution of human histone acetyltransferase HAT1.","date":"2010","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20148353","citation_count":14,"is_preprint":false},{"pmid":"38760543","id":"PMC_38760543","title":"Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38760543","citation_count":14,"is_preprint":false},{"pmid":"31784689","id":"PMC_31784689","title":"Hat1 acetylates histone H4 and modulates the transcriptional program in Drosophila embryogenesis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31784689","citation_count":13,"is_preprint":false},{"pmid":"36410688","id":"PMC_36410688","title":"Histone acetyltransferase 1 (HAT1) acetylates hypoxia-inducible factor 2 alpha (HIF2A) to execute hypoxia response.","date":"2022","source":"Biochimica et biophysica acta. 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The holoenzyme acetylates soluble (but not nucleosomal) histone H4 at Lys5 and Lys12, and histone H2A at Lys5. Both p46 and p48 bind directly to helix 1 of histone H4.\",\n      \"method\": \"Affinity purification of holoenzyme from human 293 cells, in vitro acetyltransferase assays on soluble vs. nucleosomal substrates, direct binding assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted holoenzyme, in vitro assay with defined substrates, direct binding experiments, 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 at 2.3 Å resolution revealed an elongated curved structure with AcCoA bound in a cleft on the concave surface marking the active site; a channel across the protein is the probable histone substrate binding site. The structure established Hat1 as the founding member of the GCN5-related N-acetyltransferase (GNAT) superfamily.\",\n      \"method\": \"X-ray crystallography of Hat1–AcCoA complex at 2.3 Å resolution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional interpretation, foundational structural paper\",\n      \"pmids\": [\"9727486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast HAT1 and HAT2 together constitute both the cytoplasmic type B histone acetyltransferase and a nuclear free-histone-H4-specific acetyltransferase. The catalytic subunit of both complexes is the 42 kDa HAT1 protein; the cytoplasmic complex is ~150 kDa and the nuclear complex is ~110 kDa.\",\n      \"method\": \"Biochemical fractionation of extracts from hat1, hat2, and gcn5 single and double mutant yeast strains; in vitro HAT assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic mutant panel combined with biochemical fractionation and in vitro activity assays\",\n      \"pmids\": [\"9575221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Xenopus Hat1 holoenzyme purified from oocyte nuclei contains the catalytic subunit Hat1, the retinoblastoma-associated protein RbAp48, and 14-3-3 proteins. The holoenzyme specifically acetylates free histone H4 but not nucleosomal histones. The holoenzyme is stored in vast excess in the oocyte nucleus where acetylated histones are stockpiled; following oocyte maturation it redistributes to the cytoplasm.\",\n      \"method\": \"Biochemical purification from Xenopus oocytes, in vitro acetyltransferase assays, subcellular fractionation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — purified complex, in vitro assay, fractionation with functional context\",\n      \"pmids\": [\"10529179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Acetylation of histone H4 at Lys8 and Lys16 by other acetyltransferases strongly inhibits subsequent acetylation by Hat1 at Lys5 and Lys12; pre-treatment with histone deacetylase restores Hat1 activity. Additionally, Hat1 requires positively charged amino acids (K or R) at H4 positions 8 and 16 for efficient catalysis, and phosphorylation of H4 Ser1 depresses Hat1 activity.\",\n      \"method\": \"In vitro HAT assays using synthetic H4 N-terminal peptides with defined modifications; yeast Hat1p and human HAT-B complex tested\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted assay with defined peptide substrates and multiple modifications tested\",\n      \"pmids\": [\"11585814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Hat1 preferentially acetylates Lys12 of histone H4 over Lys5 in vitro, consistent with the structural model of H4 tail binding. Deletion of hat1 in Schizosaccharomyces pombe causes increased sensitivity to the DNA-damaging agent methyl methanesulfonate even without additional histone H3 mutations, demonstrating a Hat1-dependent role in DNA damage repair that is evolutionarily conserved.\",\n      \"method\": \"In vitro HAT assays on H4 peptides; yeast genetic deletion and MMS sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro assay combined with genetic loss-of-function and defined phenotypic readout\",\n      \"pmids\": [\"17052979\"],\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). shRNA knockdown of HAT1 in HeLa cells decreased H4K5ac, H4K12ac, and H2AK5ac levels in cytosolic and insoluble nuclear protein fractions.\",\n      \"method\": \"shRNA knockdown in HeLa cells, quantification of acetylation by Western blot of histone fractions\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined modification readout, single lab\",\n      \"pmids\": [\"24682716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HAT1 is activated by CaMK2 signalling downstream of Toll-like or TNF-α receptor stimulation. Activated HAT1 then acetylates the transcriptional regulator PLZF, promoting assembly of a repressor complex (PLZF–HDAC3–NF-κB p50) that limits NF-κB-driven inflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of acetylation/phosphorylation sites, kinase activity assays, cytokine measurement upon KD/OE\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis of functional residues, and defined functional readout; single lab\",\n      \"pmids\": [\"25865065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HAT1 is part of a novel CENP-A preloading complex in Drosophila that also contains Caf1/Rbap48 and CENP-A/H4. Hat1 knockdown in S2 cells reduces incorporation of newly synthesized CENP-A into chromatin. CENP-A interacts with the Hat1 complex via its N-terminal region, which is acetylated in cytoplasmic but not nuclear CENP-A; Hat1 acetyltransferase activity is not responsible for CENP-A acetylation, suggesting a chaperone-like escort function for Hat1.\",\n      \"method\": \"Co-immunoprecipitation of Hat1 complex, RNAi knockdown with CENP-A loading readout, acetylation mapping\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and RNAi with specific phenotypic readout; single lab\",\n      \"pmids\": [\"26586808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AMPK directly phosphorylates HAT1, resulting in activation of HAT1 acetyltransferase activity. AMPK-mediated HAT1 activation promotes nucleosome remodeling and expression of mitochondrial biogenesis genes (PGC-1α, Tfam, UCP2/3) in endothelial cells and mouse aorta.\",\n      \"method\": \"In vitro AMPK phosphorylation assays, pharmacological AMPK activation in HUVECs and in vivo in mice, gene expression analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro kinase assay plus cell and in vivo functional validation; single lab\",\n      \"pmids\": [\"28143904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HAT1 binds at promoters of histone H4 genes and is required for their transcription via an acetate-sensitive promoter element. HAT1 expression is required for S-phase progression and maintenance of H3K9 acetylation at proliferation-associated loci. These data reveal a feedforward circuit in which HAT1 drives both H4 gene transcription and acetylation of nascent histones.\",\n      \"method\": \"ChIP-seq, RNA-seq, loss-of-function experiments, S-phase progression assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genome-wide methods combined with functional cell biology readouts\",\n      \"pmids\": [\"31278053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional knockout of Hat1 in mice causes early-onset aging phenotypes (lordokyphosis, muscle atrophy, cancer, paralysis), early cellular senescence, accumulation of p21, elevated reactive oxygen species, and mitochondrial defects in MEFs, indicating that Hat1 is required for normal mitochondrial function and genome stability in mammals.\",\n      \"method\": \"Conditional mouse knockout, MEF senescence assays, ROS measurement, mitochondrial function assays\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"31290578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of Hat1 in Drosophila results in near-complete loss of histone H4 K5 and K12 acetylation in embryos, identifying Hat1 as the primary H4K5 and H4K12 acetyltransferase at this developmental stage. H4K5/K12 acetylation is not required for nuclear transport of histone H4.\",\n      \"method\": \"Drosophila Hat1 loss-of-function mutant generation, Western blot of H4 acetylation marks, localization of histone H4 variant, RNA-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic KO in model organism with direct biochemical readout of enzymatic activity\",\n      \"pmids\": [\"31784689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of HAT1, which acetylates H4K5 and H4K12 during replication-coupled chromatin assembly, results in loss of chromatin accessibility in megabase-scale HAT1-dependent Accessibility Domains (HADs) that overlap with Lamin-Associated Domains. HAT1 globally represses H3K9me3 levels; HADs correspond to regions with HAT1-dependent increases in H3K9me3 peak density. HAT1 is required to maintain nuclear structure and integrity.\",\n      \"method\": \"HAT1 knockout MEFs, ATAC-seq, ChIP-seq for H3K9me3, nuclear integrity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple orthogonal genome-wide assays and structural readouts\",\n      \"pmids\": [\"34788845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HAT1 functions as a methacryltransferase, catalyzing lysine methacrylation (Kmea) on histones; SIRT2 acts as the corresponding de-methacrylase. 27 Kmea-modified histone sites were identified in HeLa cells by affinity enrichment and mass spectrometry.\",\n      \"method\": \"In vitro acetyltransferase assay with methacrylyl-CoA, pan-Kmea antibody affinity enrichment, mass spectrometry, SIRT2 de-modification assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution of novel enzymatic activity with orthogonal chemical and immunological validation\",\n      \"pmids\": [\"34961760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HAT1 directly acetylates HIF2A at K512 and K596, stabilizing HIF2A protein under normoxia and hypoxia. HAT1 and HIF2A interact physically and co-occupy the VEGFA promoter. HAT1-dependent HIF2A acetylation is required for cancer stem cell maintenance and hypoxia response in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, acetylation-mimic mutations in HIF2A, HAT1 silencing with functional readouts\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, site-directed mutagenesis, and KD with defined phenotypic readout; single lab\",\n      \"pmids\": [\"36410688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HAT1 directly acetylates ACSL4 at K383, enhancing ACSL4 protein stability by inhibiting FBXO10-mediated K48-linked ubiquitination. HDAC2 enhances ACSL4 acetylation indirectly by suppressing SIRT3 transcription. HAT1-mediated ACSL4 acetylation promotes ferroptosis sensitivity and radiosensitivity in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, site-directed mutagenesis (K383R), ubiquitination assay, in vitro and in vivo radiosensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro acetylation, mutagenesis, and ubiquitination assays with functional validation; single lab\",\n      \"pmids\": [\"40050614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Structure of the Hat1–Hat2 acetyltransferase complex bound to Asf1–H3–H4 shows that core domains of both H3 and H4 contact Hat1 and Hat2, and the H3 N-terminal tail makes extensive interaction with Hat2/RbAp46. This reveals a chaperone-passing mechanism and implicates Hat2/RbAp46/48 in transferring histones between chaperones.\",\n      \"method\": \"Cryo-EM/X-ray structure of Hat1–Hat2–Asf1–H3–H4 complex\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure with functional interpretation of histone–chaperone interactions\",\n      \"pmids\": [\"35393344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Fission yeast Hat1 (Kat1) is associated with Mis16 (RbAp46 homologue) and the Hat1 complex acetylates H4K5 and H4K12. Deletion of hat1 in S. pombe alone is sufficient to cause loss of telomeric silencing, accompanied by increased H4 acetylation in subtelomeric chromatin.\",\n      \"method\": \"Co-immunoprecipitation of Hat1 complex, in vitro HAT assay, hat1 deletion strain, telomeric silencing assay, ChIP\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — purified complex, in vitro activity assay, genetic KO with defined silencing readout\",\n      \"pmids\": [\"22771823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HAT1 is found in a complex with RIP1, RIP3, SIRT1/2, and HAT4. Mass spectrometry identified five acetylation sites in the kinase and death domains of RIP1. SIRT inhibitor MC2494 increases RIP1 acetylation; mutagenesis of acetylated lysines in RIP1 reduces RIP1-dependent cell death.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry identification of RIP1 acetylation sites, mutagenesis, cell death assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified complex and acetylation sites with mutagenesis validation; single lab\",\n      \"pmids\": [\"29535128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Unbiased proteomics of Hat1+/+ vs Hat1-/- MEFs identified 65 proteins with >2.5-fold decreased acetylation in the absence of Hat1, including the autoregulatory loop of CBP (decreased ~20-fold). Hat1-dependent acetylation targets include transcriptional regulators (p53), chromatin proteins, and mitochondrial proteins. Hat1 was detected in mitochondria by fractionation.\",\n      \"method\": \"Acetylome mass spectrometry (label-free quantitation), subcellular fractionation, Hat1 KO MEFs grown on glucose vs. galactose\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — unbiased quantitative proteomics of KO vs WT, multiple substrates identified with fractionation\",\n      \"pmids\": [\"32081014\"],\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) distributed in cytoplasm, nucleoplasm, chromatin, and nuclear matrix. Irradiation with heavy-ion particles triggers enhanced nuclear accumulation of Hat1 regulated by the PI3K and MAPK signaling pathways.\",\n      \"method\": \"Immunofluorescence, subcellular fractionation, pharmacological inhibition of PI3K/MAPK\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization by immunofluorescence/fractionation with partial signaling follow-up; single lab\",\n      \"pmids\": [\"20148353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMGB1 physically interacts with SET and HAT1 to form an HMGB1/SET/HAT1 complex that suppresses H3K9 and H3K27 acetylation, thereby repressing SASH1 transcription and promoting glycolysis and metastasis in lung adenocarcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay for H3K9ac and H3K27ac at SASH1 locus, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and ChIP with defined functional readout; single lab\",\n      \"pmids\": [\"37794134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACL subunit A2 (ACLA2) interacts with HAT1 in rice nuclei and is required for nuclear acetyl-CoA accumulation and HAT1-dependent H4K5 acetylation. The HAT1–ACLA2 module promotes cell division in developing endosperm and controls H4K5 acetylation at specific genomic loci.\",\n      \"method\": \"Co-immunoprecipitation, nuclear acetyl-CoA measurement, ChIP-seq for H4K5ac, loss-of-function mutants with cell-division readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, biochemical assay, genome-wide ChIP, and genetic KO; ortholog context (rice HAT1)\",\n      \"pmids\": [\"37277331\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HAT1 (histone acetyltransferase 1) is a type B histone acetyltransferase that forms a holoenzyme with RbAp46/48 (Hat2/Mis16) and acetylates newly synthesized histone H4 at K5 and K12 (and H2A at K5) in both cytoplasm and nucleus during replication-coupled chromatin assembly; its crystal structure defines it as the founding GNAT superfamily member, and beyond canonical histone acetylation it also catalyzes lysine methacrylation on histones, acetylates non-histone substrates including PLZF, HIF2A, and ACSL4, is activated by AMPK and CaMK2 phosphorylation, participates in a nuclear complex at histone H4 gene promoters to coordinate histone production with acetylation, is required for CENP-A loading, DNA damage repair, maintenance of heterochromatin/LAD organization, and normal mitochondrial function, with loss of Hat1 in mice causing early-onset aging and mitochondrial defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HAT1 is a type B histone acetyltransferase and founding member of the GNAT superfamily that acetylates newly synthesized, non-nucleosomal histone H4 at Lys5 and Lys12 and histone H2A at Lys5, functioning as a holoenzyme with the RbAp46/48 (Hat2/Mis16) subunit that stimulates catalytic activity and mediates histone chaperone transfer via Asf1 [PMID:9427644, PMID:35393344]. Beyond canonical histone substrates, HAT1 acetylates non-histone proteins including PLZF, HIF2A, and ACSL4 to regulate inflammatory signaling, hypoxia response, and ferroptosis sensitivity, and catalyzes lysine methacrylation on histones [PMID:25865065, PMID:36410688, PMID:40050614, PMID:34961760]. HAT1 occupies histone H4 gene promoters to drive a feedforward circuit coupling histone production with nascent histone acetylation during S phase, and is required for maintenance of chromatin accessibility at lamin-associated domains, repression of H3K9me3, telomeric silencing, DNA damage repair, and CENP-A loading [PMID:31278053, PMID:34788845, PMID:22771823, PMID:17052979, PMID:26586808]. Conditional Hat1 knockout in mice causes early-onset aging, cellular senescence, and mitochondrial dysfunction, consistent with unbiased acetylome analyses revealing broad HAT1-dependent acetylation of mitochondrial and chromatin-regulatory proteins [PMID:31290578, PMID:32081014].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining the HAT1 holoenzyme composition and substrate specificity resolved the long-standing question of which enzyme acetylates newly synthesized H4 in the cytoplasm, establishing that the catalytic subunit requires the RbAp46/48 cofactor and acts on soluble H4 K5/K12 and H2A K5 but not nucleosomal histones.\",\n      \"evidence\": \"Affinity purification from human 293 cells with in vitro acetyltransferase assays on soluble vs. nucleosomal substrates; biochemical fractionation of yeast hat1/hat2 mutants\",\n      \"pmids\": [\"9427644\", \"9575221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which p46/p48 stimulates catalysis was not resolved\", \"Whether HAT1 acts on other substrates beyond H4/H2A was unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"The crystal structure of yeast Hat1 with acetyl-CoA revealed the active-site architecture and founded the GNAT superfamily classification, providing the structural framework for understanding substrate recognition.\",\n      \"evidence\": \"X-ray crystallography of Hat1–AcCoA complex at 2.3 Å\",\n      \"pmids\": [\"9727486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure lacked the histone substrate, so the catalytic mechanism of H4 tail recognition was inferred\", \"No structure of the holoenzyme with Hat2/RbAp46\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that pre-existing H4 K8/K16 acetylation and S1 phosphorylation inhibit Hat1 activity established that Hat1 specificity depends on the modification state of its substrate, explaining why it targets only newly synthesized histones.\",\n      \"evidence\": \"In vitro HAT assays with synthetic H4 peptides bearing defined modifications\",\n      \"pmids\": [\"11585814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this cross-talk operates in vivo was not shown\", \"The structural basis for inhibition by neighboring marks was unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Hat1 deletion in fission yeast causing DNA damage sensitivity revealed that Hat1 functions extend beyond simple histone deposition acetylation to include genome maintenance, an observation conserved across species.\",\n      \"evidence\": \"S. pombe hat1 deletion with MMS sensitivity assay\",\n      \"pmids\": [\"17052979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular mechanism linking H4K5/K12 acetylation to DNA repair was not identified\", \"Whether Hat1 acts directly at damage sites was untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery that Hat1 deletion in S. pombe causes loss of telomeric silencing with increased subtelomeric H4 acetylation showed that Hat1 contributes to heterochromatin maintenance, extending its role beyond replication-coupled assembly.\",\n      \"evidence\": \"S. pombe hat1 deletion, telomeric silencing assay, ChIP for H4 acetylation\",\n      \"pmids\": [\"22771823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this reflects direct or indirect effects on heterochromatin factors was unclear\", \"Not tested in mammalian cells at this time\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies expanded HAT1 function beyond histones: one showed HAT1 acetylates the transcription factor PLZF downstream of CaMK2 to limit NF-κB inflammatory signaling, and another revealed HAT1 participates in a CENP-A preloading complex with a chaperone-like escort function independent of its acetyltransferase activity.\",\n      \"evidence\": \"Co-IP, mutagenesis of acetylation/phosphorylation sites with cytokine readouts (PLZF); RNAi of Hat1 in Drosophila S2 cells with CENP-A loading assay\",\n      \"pmids\": [\"25865065\", \"26586808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLZF acetylation sites and stoichiometry not fully mapped\", \"Chaperone function of Hat1 for CENP-A not reconstituted in vitro\", \"Both findings from single laboratories\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"AMPK-mediated phosphorylation of HAT1 linked metabolic signaling to chromatin remodeling and mitochondrial biogenesis gene expression, establishing HAT1 as a regulated node integrating energy sensing with epigenetic output.\",\n      \"evidence\": \"In vitro AMPK kinase assay, pharmacological AMPK activation in HUVECs and mouse aorta, gene expression analysis\",\n      \"pmids\": [\"28143904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific phosphorylation site(s) on HAT1 were not all mapped\", \"Whether AMPK-HAT1 axis operates in non-endothelial tissues was untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Three studies collectively established HAT1 as essential for chromatin homeostasis and organismal health: HAT1 occupies H4 gene promoters to create a feedforward loop coupling histone transcription with acetylation; Drosophila Hat1 loss abolishes nearly all H4K5/K12 acetylation; and conditional Hat1 knockout in mice causes early-onset aging, senescence, and mitochondrial dysfunction.\",\n      \"evidence\": \"ChIP-seq/RNA-seq in mammalian cells; Drosophila Hat1 KO with Western blot; conditional mouse KO with aging, senescence, ROS, and mitochondrial phenotyping\",\n      \"pmids\": [\"31278053\", \"31784689\", \"31290578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting H4K5/K12 acetylation loss to mitochondrial dysfunction not delineated\", \"Whether the aging phenotype is rescued by catalytic-dead Hat1 restoration was not tested\", \"Direct promoter targets of the feedforward loop beyond H4 genes incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Unbiased acetylome profiling of Hat1 KO MEFs revealed that HAT1 is required for acetylation of dozens of non-histone proteins including CBP, p53, and mitochondrial proteins, and that Hat1 itself localizes to mitochondria, greatly expanding its substrate repertoire.\",\n      \"evidence\": \"Quantitative acetylome mass spectrometry of Hat1+/+ vs Hat1−/− MEFs, subcellular fractionation\",\n      \"pmids\": [\"32081014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which acetylation events are direct Hat1 catalytic products vs. indirect effects is unresolved\", \"Mitochondrial import mechanism for Hat1 not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two discoveries refined HAT1's chromatin and catalytic scope: loss of HAT1 collapses chromatin accessibility at megabase-scale lamin-associated domains with concomitant H3K9me3 gain, and HAT1 was shown to catalyze lysine methacrylation, a novel acyl modification on histones.\",\n      \"evidence\": \"HAT1 KO MEFs with ATAC-seq and H3K9me3 ChIP-seq; in vitro methacrylation assay with methacrylyl-CoA and MS validation\",\n      \"pmids\": [\"34788845\", \"34961760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HAT1-dependent acetylation prevents H3K9me3 spreading is mechanistically unresolved\", \"Physiological abundance and functional significance of histone methacrylation unknown\", \"Whether methacrylation uses the same active site geometry as acetylation not structurally addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cryo-EM/crystal structure of the Hat1–Hat2–Asf1–H3–H4 complex revealed how the histone chaperone Asf1 hands off the H3–H4 dimer to the HAT1 holoenzyme, with RbAp46/Hat2 making extensive contacts with the H3 N-terminal tail, establishing a chaperone-passing mechanism for replication-coupled chromatin assembly.\",\n      \"evidence\": \"Cryo-EM and X-ray crystallography of the quaternary complex\",\n      \"pmids\": [\"35393344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream hand-off from Hat1 complex to CAF-1 not structurally captured\", \"Whether catalysis occurs during or after chaperone transfer not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"HAT1 was shown to acetylate non-histone targets HIF2A (K512/K596) and ACSL4 (K383), stabilizing these proteins and linking HAT1 to hypoxia-driven transcription and ferroptosis sensitivity in cancer.\",\n      \"evidence\": \"Co-IP, in vitro acetylation assay, site-directed mutagenesis with stability/ubiquitination readouts in glioblastoma and nasopharyngeal carcinoma cells\",\n      \"pmids\": [\"36410688\", \"40050614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both findings from single laboratories; independent confirmation needed\", \"Whether these non-histone substrates are acetylated by HAT1 in normal (non-cancer) physiology unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural and kinetic basis by which HAT1 distinguishes histone from non-histone substrates; how loss of H4K5/K12 acetylation mechanistically leads to mitochondrial dysfunction and accelerated aging; whether HAT1's mitochondrial localization reflects a direct catalytic role inside mitochondria; and what fraction of the broad acetylome changes in Hat1 KO cells represent direct versus indirect targets.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of HAT1 bound to a non-histone substrate\", \"Mitochondrial import mechanism unknown\", \"Direct vs. indirect acetylation targets not systematically distinguished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 4, 5, 6, 12, 14, 16]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4, 17]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 15, 16, 20]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 10, 13, 17, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 4, 5, 6, 10, 12, 13, 14, 17]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10, 23]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"HAT1–RbAp46/48 (HAT-B holoenzyme)\",\n      \"HAT1–Hat2–Asf1–H3–H4\",\n      \"HMGB1/SET/HAT1\"\n    ],\n    \"partners\": [\n      \"RBBP7\",\n      \"RBBP4\",\n      \"ASF1A\",\n      \"PLZF\",\n      \"HIF2A\",\n      \"ACSL4\",\n      \"HMGB1\",\n      \"SET\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}