{"gene":"KAT14","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2008,"finding":"Drosophila Atac2 (KAT14 ortholog) was identified as a second histone acetyltransferase subunit within the ATAC complex; recombinant Atac2 displays HAT activity in vitro with preference for acetylating histone H4, and mutation of Atac2 abrogated H4 lysine 16 acetylation in D. melanogaster embryos.","method":"MudPIT mass spectrometry identification of ATAC complex subunits; in vitro HAT assay with recombinant protein; in vivo mutant analysis in Drosophila embryos","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution combined with in vivo genetic mutagenesis, replicated across two organisms (Drosophila and mammalian, see PMID:19103755)","pmids":["18327268"],"is_preprint":false},{"year":2008,"finding":"The ATAC complex (containing Atac2/KAT14) does not itself exhibit nucleosome-remodeling activity, but stimulates nucleosome sliding by ISWI, SWI-SNF, and RSC complexes.","method":"In vitro nucleosome-remodeling and sliding assays with purified ATAC complex and remodeling complexes","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution assay with multiple remodeling complexes in a single rigorous study","pmids":["18327268"],"is_preprint":false},{"year":2008,"finding":"Mammalian ATAC2 (KAT14) has weak HAT activity directed toward histone H4 in vitro; depletion of ATAC2 causes disassembly of the mammalian ATAC complex, indicating an architectural/structural role in addition to its enzymatic function.","method":"In vitro HAT assay with recombinant mammalian ATAC2; ATAC2 knockdown/knockout with complex stability analysis; targeted Atac2 locus disruption in mice","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay plus genetic knockout in mice demonstrating complex disassembly; independent replication of KAT14 HAT activity from Drosophila study","pmids":["19103755"],"is_preprint":false},{"year":2008,"finding":"Targeted disruption of the Atac2 locus in mice demonstrates that the ATAC complex is essential for mammalian development, histone acetylation, cell cycle progression, and prevention of apoptosis during embryogenesis.","method":"Targeted gene disruption (knockout) in mice; phenotypic analysis of embryos including cell cycle and apoptosis assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout in mammalian model with multiple orthogonal phenotypic readouts","pmids":["19103755"],"is_preprint":false},{"year":2019,"finding":"Nuclear actin directly binds to the hATAC subunit KAT14 and modulates its histone acetyltransferase activity in vitro and in cells; actin is thus a binding partner and regulator of KAT14 enzymatic activity.","method":"AP-MS and BioID mass spectrometry; direct binding assay; in vitro HAT activity assay with and without actin; cell-based HAT activity measurements","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding established and enzymatic modulation confirmed both in vitro and in cells; two complementary MS methods used for interaction discovery; single lab","pmids":["30890647"],"is_preprint":false},{"year":2019,"finding":"Nuclear actin levels affect alternative splicing in minigene assays, likely by modulating transcription elongation rate through its interaction with the hATAC complex containing KAT14.","method":"BioID proximity labeling; minigene splicing assays with altered nuclear actin levels","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional splicing assay performed but mechanism linking KAT14 specifically to splicing is indirect (via actin/ATAC connection); single lab","pmids":["30890647"],"is_preprint":false},{"year":2000,"finding":"CRP2BP (KAT14) was identified as a novel protein that specifically interacts with the LIM1 domain of the double LIM domain protein CRP2; this interaction occurs in the cellular environment.","method":"Yeast two-hybrid interaction trap; domain mapping to LIM1 of CRP2","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid experiment with cellular confirmation but no further mechanistic follow-up in this paper","pmids":["10924333"],"is_preprint":false},{"year":2017,"finding":"KAT14 (Atac2) is SUMOylated at lysine 408 in mammalian cells and is further modified by multiple SUMO isoforms without isoform specificity.","method":"Split fluorescent protein reconstitution screen for SUMOylated proteins in living mammalian cells; site identification at K408","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — novel genetic screen with site mapping; single lab, single method for site validation","pmids":["29234079"],"is_preprint":false},{"year":2024,"finding":"KAT14 directly interacts with serum response factor (SRF) and promotes expression of α-smooth muscle actin (α-SMA) by increasing histone H4 acetylation at its promoter; this KAT14/SRF complex mediates TGF-β-induced myofibroblast differentiation and ECM production in endometrial stromal cells.","method":"Co-immunoprecipitation; ChIP for histone H4 acetylation at α-SMA promoter; KAT14 overexpression, knockout, and knockdown in cell lines and primary cells; AAV-mediated in vivo Kat14 knockdown in mouse endometriosis model; SRF knockdown/pharmacological inhibition","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing KAT14/SRF interaction, ChIP demonstrating histone H4 acetylation at specific promoter, in vitro and in vivo genetic loss-of-function with defined phenotypic rescue","pmids":["38867256"],"is_preprint":false},{"year":2023,"finding":"CRP2BP (KAT14) acts as an adaptor protein to enhance the function of CRP2 in stabilizing the MRTF/SRF/CArG-box complex and promoting SMC gene (α-SMA, collagen) expression in myofibroblasts; this adaptor function does not depend on KAT14's histone acetyltransferase activity.","method":"Cell-based functional assays with CRP2BP expression modulation; analysis of SMC gene expression; collagen substrate adhesion experiments with p38MAPK pathway analysis","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — functional cell-based assay with HAT-independence noted, but mechanistic dissection relies on expression measurements rather than direct biochemical reconstitution; single lab","pmids":["37899269"],"is_preprint":false},{"year":2013,"finding":"Drosophila Atac2 (KAT14 ortholog) functions as a regulator of intestinal stem cell (ISC) homeostasis: Atac2-RNAi or dominant-negative allele increased ISC numbers, while overexpression promoted ISC differentiation without affecting survival or lineage specification.","method":"In vivo RNAi genetic screen; dominant-negative allele expression; Atac2 overexpression in Drosophila intestine","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic loss-of-function and gain-of-function with defined cellular phenotype; multiple alleles tested; single lab","pmids":["23535028"],"is_preprint":false},{"year":2012,"finding":"Computational sequence analysis identified a PWAPA cassette (PHD-like finger + winged-helix domain) in ATAC2 (KAT14), modeled to potentially allow combined recognition of DNA and histone methylation marks, consistent with its role in the ATAC HAT complex.","method":"Sensitive sequence analysis; 3D structural modeling based on solved ASH2L PWAPA structure","journal":"Biochimie","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction and structural modeling only; no direct experimental validation of PWAPA function in KAT14","pmids":["22664638"],"is_preprint":false},{"year":2026,"finding":"KAT14 cooperates with serum response factor (SRF) to activate CDH5 (VE-cadherin) expression by acetylating histones H3K9 and H3K18 at the CDH5 locus; trophoblast-specific KAT14 knockout causes preeclampsia-like phenotypes including defective spiral artery remodeling, elevated blood pressure, and proteinuria, rescued by CDH5 overexpression.","method":"Co-immunoprecipitation; EMSA; luciferase reporter assays; ChIP for H3K9 and H3K18 acetylation; bulk RNA-seq; conditional trophoblast-specific and CDH5-Cre KAT14 knockout mouse models; in vitro proliferation, migration, invasion, and angiogenesis assays","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, EMSA, reporter assay, conditional KO mouse with rescue) establishing KAT14/SRF/CDH5 mechanism; single lab but highly rigorous","pmids":["41867034"],"is_preprint":false}],"current_model":"KAT14 (ATAC2/CRP2BP) is a histone acetyltransferase that functions as both a catalytic subunit and architectural component of the ATAC complex, acetylating histone H4 (preferentially H4K16) and also H3K9/H3K18; it cooperates with the transcription factor SRF to drive target gene expression (including α-SMA and CDH5) by depositing histone acetylation marks at specific promoters, can act as an adaptor protein (independently of its HAT activity) to stabilize the MRTF/SRF/CArG-box complex, is directly bound and regulated by nuclear actin, is SUMOylated at K408, and is essential for mammalian development, cell cycle progression, and prevention of embryonic apoptosis."},"narrative":{"mechanistic_narrative":"KAT14 (ATAC2/CRP2BP) is a histone acetyltransferase that serves as both a catalytic and an architectural subunit of the ATAC chromatin-modifying complex, where it acetylates histone H4 and, in specific gene contexts, H3K9 and H3K18 to control transcription, development, and cell-cycle progression [PMID:18327268, PMID:19103755]. Within ATAC its enzymatic activity preferentially targets H4K16 in vivo, while ATAC2 itself is required for complex integrity—its loss disassembles the mammalian ATAC complex—and the assembled complex does not remodel nucleosomes directly but stimulates the sliding activity of ISWI, SWI-SNF, and RSC remodelers [PMID:18327268, PMID:19103755]. Targeted disruption in mice establishes that KAT14 is essential for embryonic development, normal histone acetylation, cell-cycle progression, and the prevention of embryonic apoptosis [PMID:19103755]. Beyond its core ATAC role, KAT14 directly interacts with serum response factor (SRF) and deposits activating histone acetylation at target promoters, driving α-SMA expression during TGF-β-induced myofibroblast differentiation and activating CDH5 (VE-cadherin) via H3K9/H3K18 acetylation in trophoblasts, where trophoblast-specific knockout produces preeclampsia-like phenotypes rescued by CDH5 [PMID:38867256, PMID:41867034]. Its enzymatic activity is regulated by direct binding of nuclear actin [PMID:30890647], and KAT14 is SUMOylated at K408 [PMID:29234079].","teleology":[{"year":2008,"claim":"Established that KAT14/Atac2 is a catalytic histone acetyltransferase subunit of the ATAC complex, defining its core molecular activity and its preference for histone H4.","evidence":"MudPIT identification of ATAC subunits, in vitro HAT assay with recombinant Atac2, and Drosophila embryo mutant analysis showing loss of H4K16 acetylation","pmids":["18327268"],"confidence":"High","gaps":["Mechanism by which H4K16 is selected over other H4 lysines not resolved","Contribution of the second ATAC HAT subunit (GCN5) vs Atac2 to bulk acetylation not partitioned"]},{"year":2008,"claim":"Showed the ATAC complex does not itself remodel nucleosomes but functionally couples histone acetylation to ATP-dependent remodeling, situating KAT14 upstream of chromatin remodelers.","evidence":"In vitro nucleosome-sliding assays with purified ATAC and ISWI, SWI-SNF, and RSC complexes","pmids":["18327268"],"confidence":"High","gaps":["Whether KAT14 catalytic activity is required for remodeler stimulation not isolated","In vivo relevance of the ATAC-remodeler coupling not tested"]},{"year":2008,"claim":"Demonstrated KAT14 has a dual role—weak intrinsic HAT activity plus an architectural function required for ATAC complex assembly—and is essential for mammalian development.","evidence":"In vitro HAT assay with recombinant mammalian ATAC2, knockdown/knockout complex-stability analysis, and targeted Atac2 disruption in mice with embryonic cell-cycle and apoptosis phenotypes","pmids":["19103755"],"confidence":"High","gaps":["Separation of catalytic from architectural contribution to the embryonic phenotype not achieved","Direct genomic targets driving cell-cycle/apoptosis defects not mapped"]},{"year":2012,"claim":"Predicted a PWAPA (PHD-like finger plus winged-helix) cassette in KAT14 that could mediate combined DNA and histone-methylation recognition, offering a candidate chromatin-targeting module.","evidence":"Sensitive sequence analysis and 3D modeling on the solved ASH2L PWAPA structure","pmids":["22664638"],"confidence":"Low","gaps":["Purely computational with no experimental validation of PWAPA binding in KAT14","No demonstrated DNA or methyl-mark binding by the predicted domain"]},{"year":2013,"claim":"Linked KAT14 activity to tissue stem-cell control by showing Atac2 dosage tunes intestinal stem cell number versus differentiation in vivo.","evidence":"Drosophila intestinal RNAi, dominant-negative, and overexpression experiments scoring ISC homeostasis","pmids":["23535028"],"confidence":"Medium","gaps":["Molecular targets in ISCs not identified","Whether the effect requires HAT activity not tested"]},{"year":2017,"claim":"Identified a post-translational regulatory mark by mapping SUMOylation of KAT14 at K408.","evidence":"Split fluorescent protein reconstitution SUMOylation screen in living mammalian cells with site mapping","pmids":["29234079"],"confidence":"Medium","gaps":["Functional consequence of K408 SUMOylation on HAT activity or localization unknown","Single method for site validation"]},{"year":2019,"claim":"Revealed nuclear actin as a direct binding partner and regulator of KAT14 enzymatic activity, connecting actin dynamics to ATAC-mediated acetylation and potentially to co-transcriptional splicing.","evidence":"AP-MS and BioID, direct binding assays, and in vitro plus cell-based HAT activity measurements with altered actin; minigene splicing assays","pmids":["30890647"],"confidence":"High","gaps":["The actin-binding interface on KAT14 not defined","Causal link from KAT14 to splicing remains indirect via actin/elongation"]},{"year":2023,"claim":"Showed KAT14 acts as a HAT-independent adaptor, stabilizing the CRP2/MRTF/SRF/CArG-box complex to promote smooth-muscle gene expression, distinguishing a non-enzymatic function from its acetyltransferase role.","evidence":"Cell-based CRP2BP expression-modulation assays, SMC gene expression analysis, and collagen adhesion/p38MAPK experiments","pmids":["37899269"],"confidence":"Medium","gaps":["Mechanism rests on expression readouts rather than reconstituted biochemistry","Direct CRP2BP-MRTF/SRF contacts not structurally defined"]},{"year":2024,"claim":"Established a catalytic KAT14/SRF axis in which KAT14 acetylates H4 at the α-SMA promoter to drive TGF-β-induced myofibroblast differentiation and ECM production.","evidence":"Reciprocal Co-IP, ChIP for H4 acetylation at the α-SMA promoter, loss/gain-of-function in cells, and AAV-mediated Kat14 knockdown in a mouse endometriosis model","pmids":["38867256"],"confidence":"High","gaps":["How SRF recruits KAT14 to specific promoters not resolved","Genome-wide SRF-dependent KAT14 targets not mapped"]},{"year":2026,"claim":"Extended the KAT14/SRF mechanism to vascular biology, showing KAT14 activates CDH5 via H3K9/H3K18 acetylation in trophoblasts and is required to prevent preeclampsia-like pathology.","evidence":"Co-IP, EMSA, luciferase reporters, ChIP for H3K9/H3K18 acetylation, RNA-seq, conditional trophoblast- and CDH5-Cre KAT14 knockout mice, and CDH5 rescue","pmids":["41867034"],"confidence":"High","gaps":["Switch between H4 (α-SMA) and H3K9/H3K18 (CDH5) target specificity not explained","Whether ATAC-complex context is required at these loci not addressed"]},{"year":null,"claim":"How KAT14 selects its histone-target residues and is recruited to specific promoters across the ATAC complex versus SRF-cooperative and CRP2-adaptor contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of KAT14 substrate selection","Determinants partitioning HAT-dependent versus adaptor functions undefined","Genome-wide direct binding map of KAT14 lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,8,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,8,12]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,12]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,8,12]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,8,12]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3]}],"complexes":["ATAC complex"],"partners":["SRF","ACTB","CRP2 (CSRP2)","MRTF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H8E8","full_name":"Cysteine-rich protein 2-binding protein","aliases":["ADA2A-containing complex subunit 2","ATAC2","CRP2-binding partner","CRP2BP","Lysine acetyltransferase 14"],"length_aa":782,"mass_kda":88.8,"function":"Component of the ATAC complex, a complex with histone acetyltransferase activity on histones H3 and H4. May function as a scaffold for the ATAC complex to promote ATAC complex stability. Has also weak histone acetyltransferase activity toward histone H4. Required for the normal progression through G1 and G2/M phases of the cell cycle","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H8E8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT14","classification":"Not Classified","n_dependent_lines":52,"n_total_lines":1208,"dependency_fraction":0.04304635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KAT14","total_profiled":1310},"omim":[{"mim_id":"617501","title":"LYSINE ACETYLTRANSFERASE 14; KAT14","url":"https://www.omim.org/entry/617501"},{"mim_id":"601871","title":"CYSTEINE- AND GLYCINE-RICH PROTEIN 2; CSRP2","url":"https://www.omim.org/entry/601871"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KAT14"},"hgnc":{"alias_symbol":["CRP2BP","dJ717M23.1","PRO1194","ATAC2"],"prev_symbol":["CSRP2BP"]},"alphafold":{"accession":"Q9H8E8","domains":[{"cath_id":"3.90.980.20","chopping":"72-205","consensus_level":"medium","plddt":86.5577,"start":72,"end":205},{"cath_id":"-","chopping":"466-520","consensus_level":"high","plddt":82.1416,"start":466,"end":520},{"cath_id":"3.40.630.30","chopping":"555-560_571-621_635-781","consensus_level":"high","plddt":89.5755,"start":555,"end":781}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8E8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8E8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H8E8-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KAT14","jax_strain_url":"https://www.jax.org/strain/search?query=KAT14"},"sequence":{"accession":"Q9H8E8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H8E8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H8E8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H8E8"}},"corpus_meta":[{"pmid":"18327268","id":"PMC_18327268","title":"ATAC is a double histone acetyltransferase complex that stimulates nucleosome sliding.","date":"2008","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18327268","citation_count":155,"is_preprint":false},{"pmid":"19103755","id":"PMC_19103755","title":"The double-histone-acetyltransferase complex ATAC is essential for mammalian development.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19103755","citation_count":91,"is_preprint":false},{"pmid":"30890647","id":"PMC_30890647","title":"Nuclear actin interactome analysis links actin to KAT14 histone acetyl transferase and mRNA splicing.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30890647","citation_count":41,"is_preprint":false},{"pmid":"31308447","id":"PMC_31308447","title":"Selective and competitive inhibition of kynurenine aminotransferase 2 by glycyrrhizic acid and its analogues.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31308447","citation_count":26,"is_preprint":false},{"pmid":"10924333","id":"PMC_10924333","title":"The cysteine- and glycine-rich LIM domain protein CRP2 specifically interacts with a novel human protein (CRP2BP).","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10924333","citation_count":24,"is_preprint":false},{"pmid":"31247950","id":"PMC_31247950","title":"Impaired Skeletal Muscle Kynurenine Metabolism in Patients with Chronic Obstructive Pulmonary Disease.","date":"2019","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31247950","citation_count":15,"is_preprint":false},{"pmid":"31498475","id":"PMC_31498475","title":"Inhibition of histone acetylation and deacetylation enzymes affects longevity, development, and fecundity in the pea aphid (Acyrthosiphon pisum).","date":"2019","source":"Archives of insect biochemistry and physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31498475","citation_count":14,"is_preprint":false},{"pmid":"38867256","id":"PMC_38867256","title":"Lysine acetyltransferase 14 mediates TGF-β-induced fibrosis in ovarian endometrioma via co-operation with serum response factor.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38867256","citation_count":12,"is_preprint":false},{"pmid":"23535028","id":"PMC_23535028","title":"Identification of a histone acetyltransferase as a novel regulator of Drosophila intestinal stem cells.","date":"2013","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23535028","citation_count":11,"is_preprint":false},{"pmid":"31957832","id":"PMC_31957832","title":"Inhibitory effect of the Notch pathway-inhibitor DAPT on invasion and metastasis of tongue cancer via lncRNA-KAT14 regulation.","date":"2020","source":"European review for medical and pharmacological 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complexes.","date":"2012","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/22664638","citation_count":5,"is_preprint":false},{"pmid":"40437965","id":"PMC_40437965","title":"Histone and N-terminal acetyltransferases play important roles in female reproduction and embryogenesis of the red flour beetle Tribolium castaneum.","date":"2025","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40437965","citation_count":4,"is_preprint":false},{"pmid":"38255677","id":"PMC_38255677","title":"Genetic Association and Differential RNA Expression of Histone (De)Acetylation-Related Genes in Pemphigus Foliaceus-A Possible Epigenetic Effect in the Autoimmune Response.","date":"2023","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38255677","citation_count":3,"is_preprint":false},{"pmid":"37899269","id":"PMC_37899269","title":"Significance of the p38MAPK-CRP2 axis in myofibroblastic phenotypic transition.","date":"2023","source":"Cell 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cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/41121250","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11232,"output_tokens":3149,"usd":0.040466,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10547,"output_tokens":3689,"usd":0.07248,"stage2_stop_reason":"end_turn"},"total_usd":0.112946,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Atac2 (KAT14 ortholog) was identified as a second histone acetyltransferase subunit within the ATAC complex; recombinant Atac2 displays HAT activity in vitro with preference for acetylating histone H4, and mutation of Atac2 abrogated H4 lysine 16 acetylation in D. melanogaster embryos.\",\n      \"method\": \"MudPIT mass spectrometry identification of ATAC complex subunits; in vitro HAT assay with recombinant protein; in vivo mutant analysis in Drosophila embryos\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution combined with in vivo genetic mutagenesis, replicated across two organisms (Drosophila and mammalian, see PMID:19103755)\",\n      \"pmids\": [\"18327268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ATAC complex (containing Atac2/KAT14) does not itself exhibit nucleosome-remodeling activity, but stimulates nucleosome sliding by ISWI, SWI-SNF, and RSC complexes.\",\n      \"method\": \"In vitro nucleosome-remodeling and sliding assays with purified ATAC complex and remodeling complexes\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution assay with multiple remodeling complexes in a single rigorous study\",\n      \"pmids\": [\"18327268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mammalian ATAC2 (KAT14) has weak HAT activity directed toward histone H4 in vitro; depletion of ATAC2 causes disassembly of the mammalian ATAC complex, indicating an architectural/structural role in addition to its enzymatic function.\",\n      \"method\": \"In vitro HAT assay with recombinant mammalian ATAC2; ATAC2 knockdown/knockout with complex stability analysis; targeted Atac2 locus disruption in mice\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay plus genetic knockout in mice demonstrating complex disassembly; independent replication of KAT14 HAT activity from Drosophila study\",\n      \"pmids\": [\"19103755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Targeted disruption of the Atac2 locus in mice demonstrates that the ATAC complex is essential for mammalian development, histone acetylation, cell cycle progression, and prevention of apoptosis during embryogenesis.\",\n      \"method\": \"Targeted gene disruption (knockout) in mice; phenotypic analysis of embryos including cell cycle and apoptosis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout in mammalian model with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"19103755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear actin directly binds to the hATAC subunit KAT14 and modulates its histone acetyltransferase activity in vitro and in cells; actin is thus a binding partner and regulator of KAT14 enzymatic activity.\",\n      \"method\": \"AP-MS and BioID mass spectrometry; direct binding assay; in vitro HAT activity assay with and without actin; cell-based HAT activity measurements\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding established and enzymatic modulation confirmed both in vitro and in cells; two complementary MS methods used for interaction discovery; single lab\",\n      \"pmids\": [\"30890647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear actin levels affect alternative splicing in minigene assays, likely by modulating transcription elongation rate through its interaction with the hATAC complex containing KAT14.\",\n      \"method\": \"BioID proximity labeling; minigene splicing assays with altered nuclear actin levels\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional splicing assay performed but mechanism linking KAT14 specifically to splicing is indirect (via actin/ATAC connection); single lab\",\n      \"pmids\": [\"30890647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CRP2BP (KAT14) was identified as a novel protein that specifically interacts with the LIM1 domain of the double LIM domain protein CRP2; this interaction occurs in the cellular environment.\",\n      \"method\": \"Yeast two-hybrid interaction trap; domain mapping to LIM1 of CRP2\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid experiment with cellular confirmation but no further mechanistic follow-up in this paper\",\n      \"pmids\": [\"10924333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KAT14 (Atac2) is SUMOylated at lysine 408 in mammalian cells and is further modified by multiple SUMO isoforms without isoform specificity.\",\n      \"method\": \"Split fluorescent protein reconstitution screen for SUMOylated proteins in living mammalian cells; site identification at K408\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel genetic screen with site mapping; single lab, single method for site validation\",\n      \"pmids\": [\"29234079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT14 directly interacts with serum response factor (SRF) and promotes expression of α-smooth muscle actin (α-SMA) by increasing histone H4 acetylation at its promoter; this KAT14/SRF complex mediates TGF-β-induced myofibroblast differentiation and ECM production in endometrial stromal cells.\",\n      \"method\": \"Co-immunoprecipitation; ChIP for histone H4 acetylation at α-SMA promoter; KAT14 overexpression, knockout, and knockdown in cell lines and primary cells; AAV-mediated in vivo Kat14 knockdown in mouse endometriosis model; SRF knockdown/pharmacological inhibition\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing KAT14/SRF interaction, ChIP demonstrating histone H4 acetylation at specific promoter, in vitro and in vivo genetic loss-of-function with defined phenotypic rescue\",\n      \"pmids\": [\"38867256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRP2BP (KAT14) acts as an adaptor protein to enhance the function of CRP2 in stabilizing the MRTF/SRF/CArG-box complex and promoting SMC gene (α-SMA, collagen) expression in myofibroblasts; this adaptor function does not depend on KAT14's histone acetyltransferase activity.\",\n      \"method\": \"Cell-based functional assays with CRP2BP expression modulation; analysis of SMC gene expression; collagen substrate adhesion experiments with p38MAPK pathway analysis\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell-based assay with HAT-independence noted, but mechanistic dissection relies on expression measurements rather than direct biochemical reconstitution; single lab\",\n      \"pmids\": [\"37899269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Atac2 (KAT14 ortholog) functions as a regulator of intestinal stem cell (ISC) homeostasis: Atac2-RNAi or dominant-negative allele increased ISC numbers, while overexpression promoted ISC differentiation without affecting survival or lineage specification.\",\n      \"method\": \"In vivo RNAi genetic screen; dominant-negative allele expression; Atac2 overexpression in Drosophila intestine\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic loss-of-function and gain-of-function with defined cellular phenotype; multiple alleles tested; single lab\",\n      \"pmids\": [\"23535028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Computational sequence analysis identified a PWAPA cassette (PHD-like finger + winged-helix domain) in ATAC2 (KAT14), modeled to potentially allow combined recognition of DNA and histone methylation marks, consistent with its role in the ATAC HAT complex.\",\n      \"method\": \"Sensitive sequence analysis; 3D structural modeling based on solved ASH2L PWAPA structure\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction and structural modeling only; no direct experimental validation of PWAPA function in KAT14\",\n      \"pmids\": [\"22664638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KAT14 cooperates with serum response factor (SRF) to activate CDH5 (VE-cadherin) expression by acetylating histones H3K9 and H3K18 at the CDH5 locus; trophoblast-specific KAT14 knockout causes preeclampsia-like phenotypes including defective spiral artery remodeling, elevated blood pressure, and proteinuria, rescued by CDH5 overexpression.\",\n      \"method\": \"Co-immunoprecipitation; EMSA; luciferase reporter assays; ChIP for H3K9 and H3K18 acetylation; bulk RNA-seq; conditional trophoblast-specific and CDH5-Cre KAT14 knockout mouse models; in vitro proliferation, migration, invasion, and angiogenesis assays\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ChIP, EMSA, reporter assay, conditional KO mouse with rescue) establishing KAT14/SRF/CDH5 mechanism; single lab but highly rigorous\",\n      \"pmids\": [\"41867034\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT14 (ATAC2/CRP2BP) is a histone acetyltransferase that functions as both a catalytic subunit and architectural component of the ATAC complex, acetylating histone H4 (preferentially H4K16) and also H3K9/H3K18; it cooperates with the transcription factor SRF to drive target gene expression (including α-SMA and CDH5) by depositing histone acetylation marks at specific promoters, can act as an adaptor protein (independently of its HAT activity) to stabilize the MRTF/SRF/CArG-box complex, is directly bound and regulated by nuclear actin, is SUMOylated at K408, and is essential for mammalian development, cell cycle progression, and prevention of embryonic apoptosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAT14 (ATAC2/CRP2BP) is a histone acetyltransferase that serves as both a catalytic and an architectural subunit of the ATAC chromatin-modifying complex, where it acetylates histone H4 and, in specific gene contexts, H3K9 and H3K18 to control transcription, development, and cell-cycle progression [#0, #2, #3]. Within ATAC its enzymatic activity preferentially targets H4K16 in vivo, while ATAC2 itself is required for complex integrity—its loss disassembles the mammalian ATAC complex—and the assembled complex does not remodel nucleosomes directly but stimulates the sliding activity of ISWI, SWI-SNF, and RSC remodelers [#0, #1, #2]. Targeted disruption in mice establishes that KAT14 is essential for embryonic development, normal histone acetylation, cell-cycle progression, and the prevention of embryonic apoptosis [#3]. Beyond its core ATAC role, KAT14 directly interacts with serum response factor (SRF) and deposits activating histone acetylation at target promoters, driving α-SMA expression during TGF-β-induced myofibroblast differentiation and activating CDH5 (VE-cadherin) via H3K9/H3K18 acetylation in trophoblasts, where trophoblast-specific knockout produces preeclampsia-like phenotypes rescued by CDH5 [#8, #12]. Its enzymatic activity is regulated by direct binding of nuclear actin [#4], and KAT14 is SUMOylated at K408 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that KAT14/Atac2 is a catalytic histone acetyltransferase subunit of the ATAC complex, defining its core molecular activity and its preference for histone H4.\",\n      \"evidence\": \"MudPIT identification of ATAC subunits, in vitro HAT assay with recombinant Atac2, and Drosophila embryo mutant analysis showing loss of H4K16 acetylation\",\n      \"pmids\": [\"18327268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which H4K16 is selected over other H4 lysines not resolved\", \"Contribution of the second ATAC HAT subunit (GCN5) vs Atac2 to bulk acetylation not partitioned\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the ATAC complex does not itself remodel nucleosomes but functionally couples histone acetylation to ATP-dependent remodeling, situating KAT14 upstream of chromatin remodelers.\",\n      \"evidence\": \"In vitro nucleosome-sliding assays with purified ATAC and ISWI, SWI-SNF, and RSC complexes\",\n      \"pmids\": [\"18327268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KAT14 catalytic activity is required for remodeler stimulation not isolated\", \"In vivo relevance of the ATAC-remodeler coupling not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated KAT14 has a dual role—weak intrinsic HAT activity plus an architectural function required for ATAC complex assembly—and is essential for mammalian development.\",\n      \"evidence\": \"In vitro HAT assay with recombinant mammalian ATAC2, knockdown/knockout complex-stability analysis, and targeted Atac2 disruption in mice with embryonic cell-cycle and apoptosis phenotypes\",\n      \"pmids\": [\"19103755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Separation of catalytic from architectural contribution to the embryonic phenotype not achieved\", \"Direct genomic targets driving cell-cycle/apoptosis defects not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Predicted a PWAPA (PHD-like finger plus winged-helix) cassette in KAT14 that could mediate combined DNA and histone-methylation recognition, offering a candidate chromatin-targeting module.\",\n      \"evidence\": \"Sensitive sequence analysis and 3D modeling on the solved ASH2L PWAPA structure\",\n      \"pmids\": [\"22664638\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational with no experimental validation of PWAPA binding in KAT14\", \"No demonstrated DNA or methyl-mark binding by the predicted domain\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked KAT14 activity to tissue stem-cell control by showing Atac2 dosage tunes intestinal stem cell number versus differentiation in vivo.\",\n      \"evidence\": \"Drosophila intestinal RNAi, dominant-negative, and overexpression experiments scoring ISC homeostasis\",\n      \"pmids\": [\"23535028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets in ISCs not identified\", \"Whether the effect requires HAT activity not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a post-translational regulatory mark by mapping SUMOylation of KAT14 at K408.\",\n      \"evidence\": \"Split fluorescent protein reconstitution SUMOylation screen in living mammalian cells with site mapping\",\n      \"pmids\": [\"29234079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of K408 SUMOylation on HAT activity or localization unknown\", \"Single method for site validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed nuclear actin as a direct binding partner and regulator of KAT14 enzymatic activity, connecting actin dynamics to ATAC-mediated acetylation and potentially to co-transcriptional splicing.\",\n      \"evidence\": \"AP-MS and BioID, direct binding assays, and in vitro plus cell-based HAT activity measurements with altered actin; minigene splicing assays\",\n      \"pmids\": [\"30890647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The actin-binding interface on KAT14 not defined\", \"Causal link from KAT14 to splicing remains indirect via actin/elongation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed KAT14 acts as a HAT-independent adaptor, stabilizing the CRP2/MRTF/SRF/CArG-box complex to promote smooth-muscle gene expression, distinguishing a non-enzymatic function from its acetyltransferase role.\",\n      \"evidence\": \"Cell-based CRP2BP expression-modulation assays, SMC gene expression analysis, and collagen adhesion/p38MAPK experiments\",\n      \"pmids\": [\"37899269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism rests on expression readouts rather than reconstituted biochemistry\", \"Direct CRP2BP-MRTF/SRF contacts not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a catalytic KAT14/SRF axis in which KAT14 acetylates H4 at the α-SMA promoter to drive TGF-β-induced myofibroblast differentiation and ECM production.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP for H4 acetylation at the α-SMA promoter, loss/gain-of-function in cells, and AAV-mediated Kat14 knockdown in a mouse endometriosis model\",\n      \"pmids\": [\"38867256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SRF recruits KAT14 to specific promoters not resolved\", \"Genome-wide SRF-dependent KAT14 targets not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the KAT14/SRF mechanism to vascular biology, showing KAT14 activates CDH5 via H3K9/H3K18 acetylation in trophoblasts and is required to prevent preeclampsia-like pathology.\",\n      \"evidence\": \"Co-IP, EMSA, luciferase reporters, ChIP for H3K9/H3K18 acetylation, RNA-seq, conditional trophoblast- and CDH5-Cre KAT14 knockout mice, and CDH5 rescue\",\n      \"pmids\": [\"41867034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Switch between H4 (α-SMA) and H3K9/H3K18 (CDH5) target specificity not explained\", \"Whether ATAC-complex context is required at these loci not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KAT14 selects its histone-target residues and is recruited to specific promoters across the ATAC complex versus SRF-cooperative and CRP2-adaptor contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of KAT14 substrate selection\", \"Determinants partitioning HAT-dependent versus adaptor functions undefined\", \"Genome-wide direct binding map of KAT14 lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 8, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 8, 12]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 8, 12]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"ATAC complex\"],\n    \"partners\": [\"SRF\", \"ACTB\", \"CRP2 (CSRP2)\", \"MRTF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}