{"gene":"EP300","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1993,"finding":"p300 co-precipitates with TATA-binding protein (TBP) in a specific, SDS-sensitive complex, and p300-specific and TBP-specific complexes share at least two common phosphoproteins (64 kDa and 59 kDa), indicating p300 interacts with TBP and is a component of the basal transcriptional machinery.","method":"Co-immunoprecipitation, partial proteolytic digest pattern matching","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with orthogonal peptide mapping, single lab","pmids":["8502484"],"is_preprint":false},{"year":1997,"finding":"p300 binds directly to the tumor suppressor p53 in the absence of viral oncoproteins; they colocalize in the nucleus and coexist in a stable DNA-binding complex. p300 acts as a transcriptional adaptor for p53, modulating its G1 checkpoint and apoptosis functions. E1A disrupts p300/p53-dependent growth control.","method":"Co-immunoprecipitation, co-localization, functional promoter assays (p21, bax), cell-cycle and apoptosis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, co-localization, multiple functional readouts, replicated across labs","pmids":["9194565"],"is_preprint":false},{"year":2000,"finding":"p300 and CBP acetylate MyoD on two lysines at the boundary of the DNA-binding domain in vitro; this acetylation activates MyoD transcriptional activity on a muscle-specific promoter. MyoD mutants that cannot be acetylated are not functionally activated.","method":"In vitro acetylation assay, microinjection functional assay, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and functional readout, single lab","pmids":["10944526"],"is_preprint":false},{"year":2000,"finding":"Protein kinase C phosphorylates p300 at serine 89 in vivo; this phosphorylation represses the transcriptional activity of p300, representing a signal transduction pathway for PKC to regulate cell growth and differentiation.","method":"In vivo phosphorylation mapping, kinase assay, transcriptional reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo site identification with kinase assay and functional consequence, single lab","pmids":["11020388"],"is_preprint":false},{"year":2000,"finding":"EID-1 binds p300 and inhibits its histone acetyltransferase activity, thereby repressing MyoD-dependent transcription in skeletal muscle independently of its Rb-binding function.","method":"Yeast two-hybrid, co-immunoprecipitation, HAT activity assay, transcriptional reporter assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus direct HAT inhibition assay plus functional transcription readout, single lab","pmids":["11073990"],"is_preprint":false},{"year":2003,"finding":"p29ING4 and p28ING5 physically interact with p300 in vivo and enhance p300-mediated acetylation of p53 at Lys-382, thereby activating p53-dependent transcription and apoptosis.","method":"Co-immunoprecipitation, in vivo acetylation assay, transcriptional reporter assay (p21/waf1 promoter)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo acetylation with functional consequences, single lab","pmids":["12750254"],"is_preprint":false},{"year":2003,"finding":"p68 RNA helicase directly interacts with multiple domains of CBP/p300 and with RNA Pol II in vivo and in vitro; p68 stimulates CBP/p300-mediated transcription in a cooperative manner, and E1A suppression of CBP/p300 abolishes p68-driven transcription.","method":"Co-immunoprecipitation, GST pulldown, transcriptional reporter assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown with functional epistasis, single lab","pmids":["12527917"],"is_preprint":false},{"year":2005,"finding":"p300 potentiates Sox9-dependent transcription specifically on chromatinized (nucleosomal) DNA templates but not on naked DNA, and this is associated with p300-mediated histone hyperacetylation around the collagen α1(II) enhancer.","method":"In vitro transcription on chromatinized templates, recombinant protein association assay, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro transcription on chromatin templates with ChIP, single lab multiple orthogonal methods","pmids":["16109717"],"is_preprint":false},{"year":2006,"finding":"Nuclear ROCK2 associates with and phosphorylates p300 both in vitro and in cells; ROCK2-mediated phosphorylation of p300 increases its acetyltransferase activity in vitro.","method":"Co-immunoprecipitation, in vitro kinase assay, gel filtration, immunofluorescence co-localization, HAT activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro kinase and HAT assays, co-localization; single lab multiple orthogonal methods","pmids":["16574662"],"is_preprint":false},{"year":2009,"finding":"p300 and CBP function as cytoplasmic E4 polyubiquitin ligases for p53. The E3/E4 ubiquitin ligase activity resides exclusively in cytoplasmic fractions; the N-terminal ~595 aa of p300 encode both E3 and p53-directed E4 activities. CBP deficiency specifically stabilizes cytoplasmic, but not nuclear, p53.","method":"Subcellular fractionation, in vitro ubiquitination assay, co-immunoprecipitation, loss-of-function cell lines (p300/CBP-deficient)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro E4 assay, fractionation, domain mapping, loss-of-function with defined molecular phenotype, multiple orthogonal methods","pmids":["19805293"],"is_preprint":false},{"year":2009,"finding":"KAT3B/p300 acetylates transition protein 2 (TP2) more efficiently than PCAF in vitro, targeting four lysine residues in the C-terminal domain. Acetylation of TP2 by p300 reduces its DNA condensation ability and impedes its interaction with the histone chaperone NPM3.","method":"In vitro acetyltransferase assay, mass spectrometry, circular dichroism, atomic force microscopy, in vivo acetylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, mass spectrometric site mapping, and multiple structural/functional readouts, single lab","pmids":["19710011"],"is_preprint":false},{"year":2009,"finding":"The natural hydroxynaphthoquinone plumbagin inhibits p300 HAT activity in a non-competitive manner in vitro and in vivo, specifically blocking p300-mediated (but not PCAF-mediated) acetylation of p53. Site-directed mutagenesis of K1358 in the HAT domain abolishes inhibitor binding.","method":"In vitro HAT assay, in vivo p53 acetylation assay, molecular docking, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and docking, mechanistic kinetics, single lab","pmids":["19570987"],"is_preprint":false},{"year":2014,"finding":"BAG6 regulates nuclear localization of EP300; in the absence of BAG6, EP300 accumulates in the cytoplasm. BAG6 interaction with EP300 occurs in the cytoplasm and during starvation promotes EP300 translocation to the nucleus, where it acetylates p53 (pro-autophagic) while reducing cytoplasmic acetylation of ATG5, ATG7, and LC3-I (which inhibit autophagy).","method":"Subcellular fractionation, co-immunoprecipitation, loss-of-function (knockout MEFs), acetylation assays, autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation with functional consequence, Co-IP, KO model with defined molecular phenotype, single lab","pmids":["24852146"],"is_preprint":false},{"year":2015,"finding":"p300 has both acetyltransferase and crotonyltransferase activities; p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Cellular crotonyl-CoA concentration regulates histone crotonylation levels and thereby gene expression.","method":"In vitro enzymatic assay, cell-based transcription assay, genetic/environmental perturbation of crotonyl-CoA levels, ChIP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical demonstration, cell-based assays with metabolic perturbation, multiple orthogonal methods, independently reproduced","pmids":["25818647"],"is_preprint":false},{"year":2015,"finding":"DDX24 interacts with p300 and suppresses p300-mediated acetylation of p53. DDX24 overexpression inhibits the p300-p53 interaction; knockdown of DDX24 increases p53 acetylation levels, activates p53 target genes (p21, PUMA), and induces cell cycle arrest and senescence in a p53-dependent manner.","method":"Co-immunoprecipitation, RNA interference, in vivo acetylation assay, transcriptional target expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, knockdown with defined molecular and functional phenotype, single lab","pmids":["25867071"],"is_preprint":false},{"year":2017,"finding":"mTORC1 directly interacts with p300 and phosphorylates it at four serine residues in the C-terminal domain. This phosphorylation prevents the HAT domain from binding the RING domain, relieving intramolecular autoinhibition of p300. mTORC1-dependent p300 phosphorylation suppresses starvation-induced autophagy and activates lipogenesis.","method":"Co-immunoprecipitation, in vitro kinase assay, domain interaction mapping, functional autophagy and lipogenesis assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay, domain-level mechanism established, functional cellular phenotypes, single lab with multiple orthogonal methods","pmids":["29033323"],"is_preprint":false},{"year":2018,"finding":"p300 functions as a lysine 2-hydroxyisobutyryltransferase (Khib writer), targeting distinct sites from its acetylation targets. p300-catalyzed Khib on glycolytic enzymes (e.g., ENO1) regulates their catalytic activity; p300 deletion reduces Khib on these enzymes, impairs glycolysis, and sensitizes cells to glucose deprivation-induced death.","method":"In vitro enzymatic assay, quantitative proteomics (SILAC), mass spectrometry, genetic deletion (p300 KO cells), metabolic activity assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemistry, proteome-wide site mapping, KO with defined metabolic phenotype, multiple orthogonal methods","pmids":["29775581"],"is_preprint":false},{"year":2018,"finding":"Transcription factor dimerization (IRF3, STAT1) activates p300 by enabling trans-autoacetylation of p300's autoinhibitory lysine-rich loop. A crystal structure of p300 shows the autoinhibitory loop invading the active site of a neighboring HAT domain, capturing a trans-autoacetylation intermediate. The RING domain also has an autoinhibitory role requiring rearrangement for substrate access.","method":"Crystal structure, in vitro HAT assay, mutagenesis, transcription factor dimerization assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus mutagenesis in one study","pmids":["30323286"],"is_preprint":false},{"year":2018,"finding":"DYRK1A physically interacts with p300 and CBP; overexpression of DYRK1A causes hyperphosphorylation of p300/CBP. ChIP-seq shows DYRK1A co-localizes with p300/CBP at enhancers; DYRK1A knockdown reduces H3K27ac at these enhancers, indicating DYRK1A modulates p300/CBP acetyltransferase activity at enhancers.","method":"Proteomics (mass spectrometry), co-immunoprecipitation, ChIP-seq, shRNA knockdown with H3K27ac readout","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interaction, ChIP-seq, functional knockdown, single lab","pmids":["30137413"],"is_preprint":false},{"year":2019,"finding":"EP300 controls enhancer acetylation by interacting with TFAP2β, a lineage-defining transcription factor in MYCN-amplified neuroblastoma. EP300 (but not CBP) is essential for H3K27ac at core regulatory circuitry enhancers; PROTAC-mediated degradation of EP300 (JQAD1) causes loss of H3K27ac at these enhancers and rapid apoptosis in a CRBN-dependent manner.","method":"CRISPR KO, PROTAC degrader, ChIP-seq, co-immunoprecipitation, in vivo xenograft","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, chemical degrader, ChIP-seq, Co-IP, in vivo validation; multiple orthogonal methods","pmids":["34772733"],"is_preprint":false},{"year":2019,"finding":"AFF1 (a super elongation complex subunit) is site-specifically acetylated by p300; this acetylation reduces AFF1 interaction with other SEC components and impairs P-TEFb-mediated RNA Pol II CTD phosphorylation both in vitro and in vivo. Upon genotoxic stress, p300-mediated AFF1 acetylation correlates with global transcriptional downregulation, and acetylation-defective AFF1 rescues transcription.","method":"In vitro acetylation and P-TEFb kinase assays, co-immunoprecipitation, mutagenesis, ChIP, genotoxic stress experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, mutagenesis rescue, in vivo correlation, multiple orthogonal methods, single lab","pmids":["31611376"],"is_preprint":false},{"year":2020,"finding":"p300 physically interacts with NRF2 and interferes with NRF2-KEAP1 complex formation, thereby increasing NRF2 protein stability and promoting its nuclear localization. The acetyltransferase activity of p300 is indispensable for these stabilizing effects.","method":"Co-immunoprecipitation, overexpression/knockdown, nuclear fractionation, HAT-dead mutant analysis, cell viability assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, fractionation, enzymatic mutant, single lab","pmids":["32057361"],"is_preprint":false},{"year":2021,"finding":"Short-chain fatty acids propionate and butyrate (but not acetate) activate p300 acetyltransferase by being converted to acyl-CoAs that are used by p300 to catalyze auto-acylation of the autoinhibitory loop, resulting in enzyme activation and global histone acetylation—distinct from HDAC inhibition.","method":"Quantitative proteomics of histone modifications, in vitro HAT assay, metabolite tracing, genetic/chemical perturbation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical mechanism, quantitative proteomics, multiple orthogonal approaches, single lab","pmids":["34677127"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures reveal that p300/CBP recognizes histone H4 N-terminal tail acetylation via its bromodomain (and contacts DNA minor grooves outside the pocket), directing the catalytic center to non-H4 histone tails within the same nucleosome. The primary write target after reading H4NTac is H2BNT; H2BNTac promotes H2A-H2B dissociation from the nucleosome.","method":"Cryo-EM structure, in vitro acetyltransferase assay, nucleosome dissociation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with in vitro functional validation, multiple readouts","pmids":["37460559"],"is_preprint":false},{"year":2022,"finding":"The TAZ2 domain of p300 has an autoinhibitory function for HAT activity. Truncation of TAZ2 leads to hyperactive HAT and elevated H3K27ac and H3K18ac. Mechanistically, TAZ2 cooperates with neighboring HAT domains to maintain the active site in a 'closed' state; binding of transcription factors to TAZ2 or TAZ2 truncation induces a conformational opening of the active site.","method":"HAT activity assay, domain truncation mutagenesis, ChIP-seq, structural modeling, cancer mutation analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic assay with mutagenesis, structural mechanism, ChIP-seq, single lab multiple orthogonal methods","pmids":["37660055"],"is_preprint":false},{"year":2022,"finding":"NUT (in the BRD4-NUT oncoprotein) contains an acidic transcriptional activation domain that binds the TAZ2 domain of p300, allosterically activating p300. NUT-TAZ2 interaction or cancer mutations interfering with TAZ2 autoinhibition activate p300, leading to a self-organizing, acetylation-dependent feed-forward reaction enabling long-range chromatin interactions via bromodomain multivalent acetyl-lysine binding.","method":"NMR structure, in vitro acetyltransferase assay, mutagenesis, co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure, in vitro mechanism, mutagenesis, single lab multiple orthogonal methods","pmids":["36522330"],"is_preprint":false},{"year":2023,"finding":"EP300 acetylates HSPA5 (GRP78) at K353, and this acetylation reduces HSPA5's ability to inhibit lipid peroxidation, thereby promoting ferroptosis. HDAC6 limits HSPA5 acetylation and subsequent ferroptosis. Genetic or pharmacological inhibition of EP300 increases PDAC cell resistance to ferroptosis.","method":"Acetylation site mapping, mutagenesis (K353 site), genetic and pharmacological inhibition, ferroptosis assays, co-immunoprecipitation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site mutagenesis, genetic/pharmacological loss-of-function with defined phenotype, single lab","pmids":["37696842"],"is_preprint":false},{"year":2023,"finding":"p300 functions as a writer of histone crotonylation during preimplantation embryo development. P300 depletion causes developmental defects and transcriptome dysregulation. H3K18 crotonylation (H3K18cr), catalyzed by P300, localizes to active promoter regions and activates gene transcription required for embryo development.","method":"Genetic depletion (microinjection), RNA-seq, ChIP-seq, in vitro crotonylation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, genetic depletion with transcriptome and epigenome readouts, multiple orthogonal methods","pmids":["39080296"],"is_preprint":false},{"year":2023,"finding":"p300 is an obligate integrator of combinatorial transcription factor inputs for chromatin binding: systematic mutagenesis of all annotated p300 domains in live cells shows that chromatin association depends entirely on combinatorial binding through multiple TF-interaction domains. p300 acetyltransferase activity opposes its chromatin association, and N-terminal TF-interaction domains regulate catalytic activity.","method":"Single-molecule tracking (live cell imaging), domain mutagenesis, U2OS cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — single-molecule live imaging with systematic domain mutagenesis covering all annotated domains, multiple orthogonal findings in one study","pmids":["38159566"],"is_preprint":false},{"year":2023,"finding":"HDAC8 deacetylates EP300, causing its enzymatic inactivation. This inactivation increases EP300 binding to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites, altering chromatin accessibility and driving a neural crest-stem cell transcriptional state promoting melanoma brain metastasis.","method":"ATAC-seq, ChIP-seq, HDAC8 inhibitor treatment, loss-of-function, mass spectrometry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and ATAC-seq with HDAC8 manipulation, functional phenotype in vivo, single lab","pmids":["38030596"],"is_preprint":false},{"year":2023,"finding":"EP300 acetylates raptor (mTORC1 component), and nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Nutrient deprivation causes AMPK-dependent phosphorylation of p300 at serine 89, promoting its cytoplasm-to-nucleus relocalization, reducing raptor acetylation and mTORC1 activity, and activating autophagy. Nutrient repletion causes PP2A-dependent dephosphorylation of nuclear p300, enabling CRM1-dependent nuclear export and mTORC1 reactivation. In Hutchinson-Gilford progeria syndrome, progerin mislocalizes p300 to the cytoplasm, hyperactivating mTORC1.","method":"Subcellular fractionation, co-immunoprecipitation, siRNA knockdown, AMPK inhibition, CRM1 inhibition, in vivo mouse tissue analysis, patient cell lines","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — fractionation, Co-IP, multiple kinase/phosphatase manipulations, in vivo validation across tissues, disease model, multiple labs' concepts integrated","pmids":["38267537"],"is_preprint":false},{"year":2024,"finding":"p300 functions as a succinylation writer (succinyl-CoA transferase) for cytoplasmic proteins including glycolytic enzymes. EP300 deletion leads to systemic reduction of lysine succinylation; p300-mediated succinylation of PGK1 promotes glycolysis, and mutation of the succinylated site of PGK1 impairs glycolysis and lactate production in lung cancer cells.","method":"Succinylome proteomics (SILAC/MS), CRISPR KO of EP300, site mutagenesis, glycolysis/metabolomics assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteome-wide succinylome, genetic KO, site mutagenesis with functional metabolic readout, single lab","pmids":["38256128"],"is_preprint":false},{"year":2019,"finding":"EP300 acetylates FOXO3, and this acetylation promotes lapatinib sensitivity in HER2-positive breast cancer cells. Ectopic expression of wild-type but not acetylation-deficient EP300 increases acetylated-FOXO3 and lapatinib cytotoxicity; SIRT1/6 deacetylate FOXO3, counteracting EP300 activity.","method":"Ectopic expression, acetylation-deficient mutant, SIRT1/6 siRNA/inhibitor, drug sensitivity assay, ChIP","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus functional rescue, Co-IP, ChIP, single lab","pmids":["31357743"],"is_preprint":false},{"year":2019,"finding":"p300 catalyzes acetylation of NONO at K198, stabilizing NONO by antagonizing its RNF8-mediated ubiquitination/degradation. NONO stabilizes CRAF and ARAF, reactivating pERK1/2 and promoting BRAF inhibitor resistance in melanoma. ERK1/2 activation feeds back to induce p300, forming a positive feedback loop.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, ubiquitination assay, in vitro/in vivo drug resistance assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro acetylation, mutagenesis, functional phenotype in vitro and in vivo, single lab","pmids":["34017080"],"is_preprint":false},{"year":2022,"finding":"p300/CBP sustains Polycomb-group protein occupancy at repressive sites by non-enzymatic functions: CBP stabilizes RNA Pol II at PcG-bound sites and promotes Pol II pausing independently of HAT activity. CBP/Pol II pausing is required for R-loop formation and nucleosome depletion at Polycomb Response Elements.","method":"ChIP-seq, genetic manipulation in Drosophila and mouse cells, HAT-dead mutant, R-loop detection","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, HAT-dead mutant, two organism systems, single lab","pmids":["36206738"],"is_preprint":false},{"year":2023,"finding":"EP300 interacts with YAP and ZEB (via its Bromo domain and CBP/p300-HAT domain respectively) and simultaneously binds these factors to induce H3K27 acetylation at the LPCAT3 promoter, activating LPCAT3 transcription and thereby promoting ferroptosis sensitivity in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, ChIP-qPCR, dual-luciferase reporter, xenograft model, domain interaction mapping","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter with domain mapping, in vivo validation, single lab","pmids":["37166352"],"is_preprint":false}],"current_model":"EP300/p300 is a multifunctional lysine acetyltransferase (HAT/KAT3B) that acetylates histones (H3K27, H3K18, H4, H2B) and diverse non-histone substrates (p53, MyoD, FOXO3, AFF1, HSPA5, TP2, raptor, NONO) using multiple acyl-CoA donors (acetyl-, crotonyl-, 2-hydroxyisobutyryl-, succinyl-CoA), and whose catalytic activity is regulated by autoinhibitory intramolecular interactions (RING domain, TAZ2 domain, autoinhibitory lysine-rich loop) that are relieved by trans-autoacetylation triggered by dimerized transcription factors, by mTORC1-mediated phosphorylation, by AMPK-mediated phosphorylation at S89 (which also controls nucleocytoplasmic shuttling to regulate mTORC1 and autophagy), and by PKC-mediated phosphorylation at S89 (repressive); p300 acts as a scaffold bridging sequence-specific transcription factors (p53, Sox9, AR, NRF2, IRF3, STAT1, TFAP2β) to the basal transcription machinery (TBP), and as a cytoplasmic E4 ubiquitin ligase for p53 degradation—functions compartmentalized from its nuclear co-activator roles."},"narrative":{"mechanistic_narrative":"EP300/p300 is a multifunctional lysine acyltransferase that writes activating chromatin marks and acts as a transcriptional adaptor bridging sequence-specific transcription factors to the basal machinery, where it was first identified as a TBP-associated component [PMID:8502484] and a direct p53-binding co-activator controlling cell-cycle checkpoint and apoptotic programs [PMID:9194565]. Beyond histones (H3K27, H3K18, H2B), p300 acetylates a broad non-histone substrate set—MyoD [PMID:10944526], transition protein TP2 [PMID:19710011], the elongation factor AFF1 [PMID:31611376], NRF2 [PMID:32057361], NONO [PMID:34017080], FOXO3 [PMID:31357743], HSPA5 [PMID:37696842] and the mTORC1 component raptor [PMID:38267537]—coupling these modifications to muscle differentiation, chromatin condensation, transcriptional elongation, redox signaling, drug resistance and ferroptosis. Cryo-EM shows that p300 reads pre-existing H4 N-terminal acetylation through its bromodomain and directs catalysis to H2B tails to drive H2A-H2B eviction within the same nucleosome [PMID:37460559], and it potentiates transcription specifically on chromatinized templates [PMID:16109717]. It also functions as a promiscuous acyltransferase, installing crotonylation [PMID:25818647, PMID:39080296], 2-hydroxyisobutyrylation [PMID:29775581] and succinylation [PMID:38256128] on histones and cytoplasmic glycolytic enzymes, linking acyl-CoA metabolism to gene expression and metabolic flux. p300 catalytic activity is held in check by intramolecular autoinhibition involving an autoinhibitory lysine-rich loop, the RING domain and the TAZ2 domain [PMID:30323286, PMID:37660055, PMID:36522330]; this brake is relieved by transcription-factor-dimerization-driven trans-autoacetylation [PMID:30323286], by metabolite-derived acyl-CoAs that auto-acylate the loop [PMID:34677127], and by mTORC1 phosphorylation that prevents HAT-RING contact [PMID:29033323]. Chromatin engagement is itself dictated by combinatorial transcription-factor inputs, with acetyltransferase activity opposing stable chromatin association [PMID:38159566]. A spatially distinct cytoplasmic pool acts as an E3/E4 polyubiquitin ligase for p53 [PMID:19805293], and AMPK/PP2A-controlled phosphorylation at Ser89 governs nucleocytoplasmic shuttling that tunes raptor acetylation, mTORC1 activity and autophagy [PMID:38267537].","teleology":[{"year":1993,"claim":"Established p300 as a physical component of the basal transcription apparatus, providing the first mechanistic anchor for its co-activator role.","evidence":"Co-immunoprecipitation with TBP and proteolytic peptide mapping","pmids":["8502484"],"confidence":"Medium","gaps":["Did not define the functional consequence of the TBP interaction","Shared phosphoproteins (64/59 kDa) left unidentified"]},{"year":1997,"claim":"Showed p300 directly binds p53 and serves as a transcriptional adaptor controlling growth arrest and apoptosis, connecting it to tumor suppressor signaling.","evidence":"Reciprocal Co-IP, co-localization, and p21/bax promoter and cell-cycle/apoptosis assays","pmids":["9194565"],"confidence":"High","gaps":["Did not resolve whether acetylation or scaffolding drives the effect","No structural basis for the interaction"]},{"year":2000,"claim":"Demonstrated that p300 acetylation of a non-histone substrate (MyoD) can directly activate that factor, broadening its enzymatic role beyond chromatin.","evidence":"In vitro acetylation, microinjection functional assay, acetylation-site mutagenesis","pmids":["10944526"],"confidence":"High","gaps":["In vitro acetylation site relevance in vivo not fully mapped","Did not address chromatin context at the muscle promoter"]},{"year":2000,"claim":"Identified the first regulatory inputs onto p300—PKC phosphorylation at S89 (repressive) and the EID-1 HAT inhibitor—revealing that p300 activity is signal-controlled.","evidence":"In vivo phospho-site mapping plus kinase/reporter assays; yeast two-hybrid plus HAT inhibition assay","pmids":["11020388","11073990"],"confidence":"Medium","gaps":["Structural mechanism of S89 phosphorylation effect not defined","EID-1 inhibition mechanism on the HAT domain unresolved"]},{"year":2005,"claim":"Established that p300 co-activation requires a nucleosomal template, linking its function mechanistically to histone hyperacetylation rather than naked-DNA transcription.","evidence":"Reconstituted in vitro transcription on chromatinized templates with Sox9 and ChIP","pmids":["16109717"],"confidence":"High","gaps":["Specific histone residues responsible not pinned down here","Generalizability beyond the collagen enhancer untested"]},{"year":2009,"claim":"Revealed a compartment-specific moonlighting function: cytoplasmic p300/CBP act as an E4 polyubiquitin ligase that degrades p53, separating nuclear co-activation from cytoplasmic destruction.","evidence":"Subcellular fractionation, in vitro ubiquitination, domain mapping, p300/CBP-deficient cells","pmids":["19805293"],"confidence":"High","gaps":["Catalytic mechanism of E4 activity within the N-terminal region not structurally defined","Regulation switching between HAT and ligase roles unclear"]},{"year":2009,"claim":"Extended the non-histone substrate repertoire and showed acetylation can disable a substrate's biophysical function, with TP2 acetylation reducing DNA condensation.","evidence":"In vitro acetylation, MS site mapping, CD and AFM, in vivo acetylation","pmids":["19710011"],"confidence":"High","gaps":["Physiological role of TP2 acetylation during spermiogenesis not demonstrated in vivo"]},{"year":2009,"claim":"Provided a selective small-molecule (plumbagin) inhibitor and identified K1358 as critical for inhibitor binding, supporting the HAT domain as a druggable target.","evidence":"In vitro HAT assay, in vivo p53 acetylation, docking, site-directed mutagenesis","pmids":["19570987"],"confidence":"High","gaps":["Selectivity over other acyltransferases in cells incomplete","Non-competitive mechanism not crystallographically resolved"]},{"year":2014,"claim":"Defined BAG6 as a controller of p300 nucleocytoplasmic distribution coupling p300 localization to autophagy regulation via differential substrate acetylation.","evidence":"Fractionation, Co-IP, knockout MEFs, acetylation and autophagy assays","pmids":["24852146"],"confidence":"Medium","gaps":["Direct mechanism of BAG6-driven import not structurally defined","Relationship to later AMPK/S89 shuttling model not integrated here"]},{"year":2015,"claim":"Showed p300 is a crotonyltransferase whose activity is governed by cellular acyl-CoA levels, establishing it as a metabolic sensor that converts metabolite flux into transcriptional output.","evidence":"In vitro enzymatic assay, cell-based transcription, crotonyl-CoA perturbation, ChIP","pmids":["25818647"],"confidence":"High","gaps":["Genomic distribution of crotonylation versus acetylation not fully mapped here","Selectivity determinants for acyl-CoA choice unresolved"]},{"year":2015,"claim":"Identified DDX24 as a negative regulator that blocks the p300-p53 interaction, adding to the network controlling p53 acetylation and senescence.","evidence":"Co-IP, RNAi, in vivo acetylation, p53 target expression","pmids":["25867071"],"confidence":"Medium","gaps":["Direct versus indirect competition for p53 binding not distinguished","Single-lab finding without reciprocal structural data"]},{"year":2017,"claim":"Defined a direct mTORC1-to-p300 phosphorylation axis that relieves intramolecular HAT-RING autoinhibition, linking nutrient signaling to p300 activation, autophagy suppression and lipogenesis.","evidence":"Co-IP, in vitro kinase assay, domain-interaction mapping, autophagy/lipogenesis assays","pmids":["29033323"],"confidence":"High","gaps":["Phospho-site to conformational change link inferred, not structurally captured","Crosstalk with other autoinhibitory domains not addressed"]},{"year":2018,"claim":"Captured the structural basis of p300 autoactivation: transcription-factor dimerization triggers trans-autoacetylation of an autoinhibitory loop that invades a neighboring active site.","evidence":"Crystal structure, in vitro HAT assay, mutagenesis, TF dimerization assays","pmids":["30323286"],"confidence":"High","gaps":["In vivo kinetics of the trans-autoacetylation reaction not quantified","RING-domain rearrangement mechanism only partially defined"]},{"year":2018,"claim":"Discovered p300 as a 2-hydroxyisobutyryltransferase acting on glycolytic enzymes, directly coupling its enzymatic activity to metabolic flux and glucose-deprivation survival.","evidence":"In vitro assay, SILAC proteomics, MS, p300 KO cells, metabolic assays","pmids":["29775581"],"confidence":"High","gaps":["Stoichiometry and reversibility of cytoplasmic Khib not defined","Site selectivity rules across substrates unresolved"]},{"year":2018,"claim":"Implicated DYRK1A as a kinase modulating p300/CBP enhancer activity, adding an enhancer-localized phospho-regulatory input to the network.","evidence":"MS interaction, Co-IP, ChIP-seq, shRNA with H3K27ac readout","pmids":["30137413"],"confidence":"Medium","gaps":["Direct phosphorylation sites on p300 not mapped","Causality between phosphorylation and activity not biochemically isolated"]},{"year":2019,"claim":"Established a non-redundant, druggable role for EP300 (over CBP) in sustaining core regulatory enhancers, validated by selective PROTAC degradation causing enhancer collapse and apoptosis.","evidence":"CRISPR KO, JQAD1 PROTAC, ChIP-seq, Co-IP, xenograft","pmids":["34772733"],"confidence":"High","gaps":["Molecular basis of EP300 vs CBP specificity at these enhancers unresolved","Generalizability beyond MYCN-amplified neuroblastoma untested here"]},{"year":2019,"claim":"Showed p300 acetylation of AFF1 dampens super-elongation-complex assembly and P-TEFb-dependent Pol II CTD phosphorylation, revealing a repressive role in transcriptional elongation under genotoxic stress.","evidence":"In vitro acetylation and P-TEFb kinase assays, mutagenesis rescue, ChIP","pmids":["31611376"],"confidence":"High","gaps":["Genome-wide scope of stress-induced AFF1 acetylation not mapped","Interplay with p300's activating chromatin functions unresolved"]},{"year":2019,"claim":"Connected p300 acetylation to drug-response phenotypes, with FOXO3 acetylation promoting lapatinib sensitivity and NONO acetylation driving BRAF-inhibitor resistance via a p300-ERK feedback loop.","evidence":"Acetylation-deficient mutants, SIRT manipulation, ubiquitination assays, drug-sensitivity and in vivo resistance assays","pmids":["31357743","34017080"],"confidence":"Medium","gaps":["Context-dependence of opposing drug-response outcomes not reconciled","Single-lab findings without independent replication"]},{"year":2020,"claim":"Showed p300 stabilizes NRF2 by disrupting NRF2-KEAP1 complex formation in a HAT-dependent manner, linking p300 to oxidative-stress transcriptional responses.","evidence":"Co-IP, knockdown/overexpression, fractionation, HAT-dead mutant","pmids":["32057361"],"confidence":"Medium","gaps":["NRF2 acetylation site(s) not mapped","Direct versus indirect KEAP1 interference not resolved"]},{"year":2021,"claim":"Established that short-chain fatty acid-derived acyl-CoAs activate p300 by auto-acylating its autoinhibitory loop, mechanistically distinct from HDAC inhibition.","evidence":"Histone-modification proteomics, in vitro HAT assay, metabolite tracing, genetic/chemical perturbation","pmids":["34677127"],"confidence":"High","gaps":["Relative contribution to histone acetylation versus HDAC inhibition in vivo not fully partitioned"]},{"year":2022,"claim":"Resolved how p300 reads and writes within a nucleosome: bromodomain recognition of H4 N-terminal acetylation directs catalysis to H2B tails, promoting H2A-H2B eviction.","evidence":"Cryo-EM structure, in vitro acetylation, nucleosome dissociation assay","pmids":["37460559"],"confidence":"High","gaps":["Source of the initiating H4 acetylation not defined","Functional impact on transcription in cells not directly tested here"]},{"year":2022,"claim":"Defined the TAZ2 domain as a second autoinhibitory module whose conformational opening by transcription-factor binding (including oncogenic NUT) activates the HAT, unifying autoinhibition with feed-forward chromatin activation.","evidence":"HAT assays, domain truncation, ChIP-seq, NMR structure, cancer-mutation analysis","pmids":["37660055","36522330"],"confidence":"High","gaps":["Quantitative interplay among RING, loop, and TAZ2 autoinhibition not integrated","How cancer mutations map onto each brake incompletely defined"]},{"year":2022,"claim":"Uncovered a non-enzymatic role for p300/CBP in sustaining Polycomb repression via Pol II pausing and R-loop formation, showing its function is not solely acetyltransferase-dependent.","evidence":"ChIP-seq, HAT-dead mutant, Drosophila and mouse cells, R-loop detection","pmids":["36206738"],"confidence":"Medium","gaps":["Structural basis of HAT-independent Pol II stabilization unknown","Direct versus indirect contribution to PcG occupancy unresolved"]},{"year":2023,"claim":"Demonstrated that p300 chromatin association is dictated by combinatorial transcription-factor inputs and is opposed by its own catalytic activity, reframing how p300 is recruited genome-wide.","evidence":"Single-molecule tracking, systematic domain mutagenesis, U2OS cells","pmids":["38159566"],"confidence":"High","gaps":["Identity of the dominant TF combinations at specific loci not enumerated","Mechanism by which acetylation reduces chromatin dwell-time unresolved"]},{"year":2023,"claim":"Defined deacetylase-mediated control of p300 output, with HDAC8 inactivating EP300 to redirect its TF-site occupancy and HDAC6/SIRT counter-regulating substrate acetylation in disease contexts.","evidence":"ATAC-seq, ChIP-seq, MS, HDAC inhibitor/loss-of-function, in vivo metastasis models","pmids":["38030596","37696842"],"confidence":"Medium","gaps":["Autoacetylation sites removed by HDAC8 not fully mapped","Generalizability beyond melanoma/PDAC contexts untested"]},{"year":2023,"claim":"Established p300 as a writer of histone crotonylation (H3K18cr) essential for preimplantation embryo development, demonstrating developmental requirement for its acyltransferase function.","evidence":"Genetic depletion, RNA-seq, ChIP-seq, in vitro crotonylation assay","pmids":["39080296"],"confidence":"High","gaps":["Relative developmental contribution of crotonylation versus acetylation not partitioned"]},{"year":2023,"claim":"Linked p300 acetylation to ferroptosis through HSPA5-K353 acetylation and YAP/ZEB-dependent LPCAT3 enhancer activation, connecting p300 to lipid-peroxidation cell-death control.","evidence":"Site mapping/mutagenesis, Co-IP, ChIP, luciferase reporter, ferroptosis assays, xenograft","pmids":["37696842","37166352"],"confidence":"Medium","gaps":["Context-dependence of pro- versus anti-ferroptotic outcomes not reconciled","Single-lab findings per substrate"]},{"year":2024,"claim":"Integrated p300 localization into nutrient signaling: AMPK-dependent S89 phosphorylation drives nuclear entry that reduces raptor acetylation and mTORC1 activity to activate autophagy, with PP2A/CRM1 reversing the cycle, and progerin-driven mislocalization implicating the axis in Hutchinson-Gilford progeria.","evidence":"Fractionation, Co-IP, kinase/phosphatase and CRM1 manipulations, mouse tissue, patient cells","pmids":["38267537"],"confidence":"High","gaps":["Structural basis of S89-dependent shuttling not defined","Reconciliation with earlier PKC-S89 repressive model not addressed"]},{"year":2024,"claim":"Showed p300 functions as a succinyltransferase on cytoplasmic glycolytic enzymes (PGK1), establishing succinylation as another metabolic-regulatory output of p300 in cancer.","evidence":"Succinylome proteomics, CRISPR KO, site mutagenesis, glycolysis/metabolomics","pmids":["38256128"],"confidence":"Medium","gaps":["Cytoplasmic substrate selectivity rules undefined","Reversibility/desuccinylase counterpart not identified"]},{"year":null,"claim":"How the multiple autoinhibitory brakes (lysine-rich loop, RING, TAZ2), diverse acyl-CoA selectivity, compartment-specific catalytic versus ligase functions, and combinatorial TF-driven recruitment are coordinated into a single integrated regulatory logic remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking acyl-CoA choice to substrate/site selection","Switch governing nuclear HAT versus cytoplasmic E4 ligase roles undefined","Quantitative hierarchy among the three autoinhibitory domains unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,10,20,21,26,32,33]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[13,16,22,27,31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[23,7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,7,17,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,12,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9,12,16,30,31]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7,23,27]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7,17,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13,23,24,27,34]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12,15,30]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[16,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,26,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,21,30,33]}],"complexes":[],"partners":["TP53","TBP","MYOD1","AFF1","NRF2","NONO","TFAP2B","RPTOR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q09472","full_name":"Histone acetyltransferase p300","aliases":["E1A-associated protein p300","Histone butyryltransferase p300","Histone crotonyltransferase p300","Protein 2-hydroxyisobutyryltransferase p300","Protein isonicotinyltransferase p300","Protein lactyltransferas p300","Protein propionyltransferase p300"],"length_aa":2414,"mass_kda":264.2,"function":"Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:40240600, PubMed:8945521). Acetylates all four core histones in nucleosomes (PubMed:23415232, PubMed:23934153, PubMed:8945521). Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability (PubMed:23415232). Mediates acetylation of histone H3 at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac, respectively) (PubMed:21131905, PubMed:23911289). Also able to acetylate histone lysine residues that are already monomethylated on the same side chain to form N6-acetyl-N6-methyllysine (Kacme), an epigenetic mark of active chromatin associated with increased transcriptional initiation (PubMed:37731000). Catalyzes formation of histone H4 acetyl-methylated at 'Lys-5' and 'Lys-12' (H4K5acme and H4K12acme, respectively) (PubMed:37731000). In response to DNA damage, catalyzes acetylation of histone H1 at 'Lys-75' (H1K75ac) following histone H1 deamidation by CTPS1, increasing chromatin accessibility to facilitate the recruitment of DNA repair proteins (PubMed:40240600). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRDM16, PRMT1, SIRT2, STAT3, ZNF76 or GLUL (PubMed:12929931, PubMed:15653507, PubMed:16285960, PubMed:16337145, PubMed:16762839, PubMed:18722353, PubMed:18782771, PubMed:26990986). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Following DNA damage, forms a stress-responsive p53/TP53 coactivator complex with JMY which mediates p53/TP53 acetylation, thereby increasing p53/TP53-dependent transcription and apoptosis (PubMed:11511361, PubMed:15448695). Promotes chromatin acetylation in heat shock responsive HSP genes during the heat shock response (HSR), thereby stimulating HSR transcription (PubMed:18451878). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acetylates 'Lys-247' of EGR2 (By similarity). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement (PubMed:14752053). Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates STAT3 at different sites, promoting both STAT3 dimerization and activation and recruitment to chromatin (PubMed:15653507, PubMed:16285960, PubMed:18782771). Acetylates BCL6 which disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degradation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). Acetylates GABPB1, impairing GABPB1 heterotetramerization and activity (By similarity). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097). Acetylates RXRA and RXRG (PubMed:17761950). Acetylates isoform M2 of PKM (PKM2), promoting its homodimerization and conversion into a protein kinase (PubMed:24120661). Acetylates RPTOR in response to leucine, leading to activation of the mTORC1 complex (PubMed:30197302, PubMed:32561715). Acetylates RICTOR, leading to activation of the mTORC2 complex (PubMed:22084251). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREBBP (PubMed:8917528). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA), 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), lactoyl-CoA, propanoyl-CoA (propionyl-CoA) or isonicotinyl-CoA, and is able to mediate protein crotonylation, butyrylation, 2-hydroxyisobutyrylation, lactylation, propionylation or isonicotinylation, respectively (PubMed:17267393, PubMed:25818647, PubMed:29775581, PubMed:31645732, PubMed:34545082). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (2E)-butenoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Catalyzes histone lactylation in macrophages by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription (PubMed:31645732). Acts as a protein-lysine 2-hydroxyisobutyryltransferase; regulates glycolysis by mediating 2-hydroxyisobutyrylation of glycolytic enzymes (PubMed:29775581). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493) (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein","subcellular_location":"Cytoplasm; Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q09472/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EP300","classification":"Not Classified","n_dependent_lines":434,"n_total_lines":1208,"dependency_fraction":0.35927152317880795},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EP300","total_profiled":1310},"omim":[{"mim_id":"618489","title":"BROMODOMAIN-CONTAINING PROTEIN 7; BRD7","url":"https://www.omim.org/entry/618489"},{"mim_id":"618333","title":"MENKE-HENNEKAM SYNDROME 2; MKHK2","url":"https://www.omim.org/entry/618333"},{"mim_id":"618332","title":"MENKE-HENNEKAM SYNDROME 1; MKHK1","url":"https://www.omim.org/entry/618332"},{"mim_id":"617650","title":"PTGS2 ANTISENSE NFKB1 COMPLEX-MEDIATED EXPRESSION REGULATOR RNA, NONCODING; PACERR","url":"https://www.omim.org/entry/617650"},{"mim_id":"617544","title":"LONG INTERGENIC NONCODING RNA 672; LINC00672","url":"https://www.omim.org/entry/617544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EP300"},"hgnc":{"alias_symbol":["p300","KAT3B"],"prev_symbol":[]},"alphafold":{"accession":"Q09472","domains":[{"cath_id":"1.20.1020.10","chopping":"330-420","consensus_level":"medium","plddt":81.0597,"start":330,"end":420},{"cath_id":"1.10.246.20","chopping":"577-656","consensus_level":"medium","plddt":80.4281,"start":577,"end":656},{"cath_id":"1.20.920.10","chopping":"1048-1168","consensus_level":"medium","plddt":94.4323,"start":1048,"end":1168},{"cath_id":"2.10.110.40","chopping":"1173-1239","consensus_level":"medium","plddt":78.0513,"start":1173,"end":1239},{"cath_id":"3.30.40.10","chopping":"1241-1286","consensus_level":"medium","plddt":93.8013,"start":1241,"end":1286},{"cath_id":"-","chopping":"1290-1528_1576-1664","consensus_level":"high","plddt":92.7891,"start":1290,"end":1664},{"cath_id":"3.30.60.90","chopping":"1667-1710","consensus_level":"medium","plddt":73.9223,"start":1667,"end":1710},{"cath_id":"1.20.1020.10","chopping":"1736-1832","consensus_level":"medium","plddt":77.5565,"start":1736,"end":1832}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09472","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q09472-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q09472-F1-predicted_aligned_error_v6.png","plddt_mean":53.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EP300","jax_strain_url":"https://www.jax.org/strain/search?query=EP300"},"sequence":{"accession":"Q09472","fasta_url":"https://rest.uniprot.org/uniprotkb/Q09472.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q09472/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09472"}},"corpus_meta":[{"pmid":"11559745","id":"PMC_11559745","title":"p300/CBP 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they colocalize in the nucleus and coexist in a stable DNA-binding complex. p300 acts as a transcriptional adaptor for p53, modulating its G1 checkpoint and apoptosis functions. E1A disrupts p300/p53-dependent growth control.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, functional promoter assays (p21, bax), cell-cycle and apoptosis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, co-localization, multiple functional readouts, replicated across labs\",\n      \"pmids\": [\"9194565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"p300 and CBP acetylate MyoD on two lysines at the boundary of the DNA-binding domain in vitro; this acetylation activates MyoD transcriptional activity on a muscle-specific promoter. MyoD mutants that cannot be acetylated are not functionally activated.\",\n      \"method\": \"In vitro acetylation assay, microinjection functional assay, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and functional readout, single lab\",\n      \"pmids\": [\"10944526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Protein kinase C phosphorylates p300 at serine 89 in vivo; this phosphorylation represses the transcriptional activity of p300, representing a signal transduction pathway for PKC to regulate cell growth and differentiation.\",\n      \"method\": \"In vivo phosphorylation mapping, kinase assay, transcriptional reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo site identification with kinase assay and functional consequence, single lab\",\n      \"pmids\": [\"11020388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"EID-1 binds p300 and inhibits its histone acetyltransferase activity, thereby repressing MyoD-dependent transcription in skeletal muscle independently of its Rb-binding function.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, HAT activity assay, transcriptional reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus direct HAT inhibition assay plus functional transcription readout, single lab\",\n      \"pmids\": [\"11073990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p29ING4 and p28ING5 physically interact with p300 in vivo and enhance p300-mediated acetylation of p53 at Lys-382, thereby activating p53-dependent transcription and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vivo acetylation assay, transcriptional reporter assay (p21/waf1 promoter)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo acetylation with functional consequences, single lab\",\n      \"pmids\": [\"12750254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"p68 RNA helicase directly interacts with multiple domains of CBP/p300 and with RNA Pol II in vivo and in vitro; p68 stimulates CBP/p300-mediated transcription in a cooperative manner, and E1A suppression of CBP/p300 abolishes p68-driven transcription.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, transcriptional reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown with functional epistasis, single lab\",\n      \"pmids\": [\"12527917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p300 potentiates Sox9-dependent transcription specifically on chromatinized (nucleosomal) DNA templates but not on naked DNA, and this is associated with p300-mediated histone hyperacetylation around the collagen α1(II) enhancer.\",\n      \"method\": \"In vitro transcription on chromatinized templates, recombinant protein association assay, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro transcription on chromatin templates with ChIP, single lab multiple orthogonal methods\",\n      \"pmids\": [\"16109717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Nuclear ROCK2 associates with and phosphorylates p300 both in vitro and in cells; ROCK2-mediated phosphorylation of p300 increases its acetyltransferase activity in vitro.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, gel filtration, immunofluorescence co-localization, HAT activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro kinase and HAT assays, co-localization; single lab multiple orthogonal methods\",\n      \"pmids\": [\"16574662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p300 and CBP function as cytoplasmic E4 polyubiquitin ligases for p53. The E3/E4 ubiquitin ligase activity resides exclusively in cytoplasmic fractions; the N-terminal ~595 aa of p300 encode both E3 and p53-directed E4 activities. CBP deficiency specifically stabilizes cytoplasmic, but not nuclear, p53.\",\n      \"method\": \"Subcellular fractionation, in vitro ubiquitination assay, co-immunoprecipitation, loss-of-function cell lines (p300/CBP-deficient)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro E4 assay, fractionation, domain mapping, loss-of-function with defined molecular phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"19805293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KAT3B/p300 acetylates transition protein 2 (TP2) more efficiently than PCAF in vitro, targeting four lysine residues in the C-terminal domain. Acetylation of TP2 by p300 reduces its DNA condensation ability and impedes its interaction with the histone chaperone NPM3.\",\n      \"method\": \"In vitro acetyltransferase assay, mass spectrometry, circular dichroism, atomic force microscopy, in vivo acetylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, mass spectrometric site mapping, and multiple structural/functional readouts, single lab\",\n      \"pmids\": [\"19710011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The natural hydroxynaphthoquinone plumbagin inhibits p300 HAT activity in a non-competitive manner in vitro and in vivo, specifically blocking p300-mediated (but not PCAF-mediated) acetylation of p53. Site-directed mutagenesis of K1358 in the HAT domain abolishes inhibitor binding.\",\n      \"method\": \"In vitro HAT assay, in vivo p53 acetylation assay, molecular docking, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and docking, mechanistic kinetics, single lab\",\n      \"pmids\": [\"19570987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BAG6 regulates nuclear localization of EP300; in the absence of BAG6, EP300 accumulates in the cytoplasm. BAG6 interaction with EP300 occurs in the cytoplasm and during starvation promotes EP300 translocation to the nucleus, where it acetylates p53 (pro-autophagic) while reducing cytoplasmic acetylation of ATG5, ATG7, and LC3-I (which inhibit autophagy).\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, loss-of-function (knockout MEFs), acetylation assays, autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation with functional consequence, Co-IP, KO model with defined molecular phenotype, single lab\",\n      \"pmids\": [\"24852146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p300 has both acetyltransferase and crotonyltransferase activities; p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Cellular crotonyl-CoA concentration regulates histone crotonylation levels and thereby gene expression.\",\n      \"method\": \"In vitro enzymatic assay, cell-based transcription assay, genetic/environmental perturbation of crotonyl-CoA levels, ChIP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical demonstration, cell-based assays with metabolic perturbation, multiple orthogonal methods, independently reproduced\",\n      \"pmids\": [\"25818647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX24 interacts with p300 and suppresses p300-mediated acetylation of p53. DDX24 overexpression inhibits the p300-p53 interaction; knockdown of DDX24 increases p53 acetylation levels, activates p53 target genes (p21, PUMA), and induces cell cycle arrest and senescence in a p53-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference, in vivo acetylation assay, transcriptional target expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, knockdown with defined molecular and functional phenotype, single lab\",\n      \"pmids\": [\"25867071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"mTORC1 directly interacts with p300 and phosphorylates it at four serine residues in the C-terminal domain. This phosphorylation prevents the HAT domain from binding the RING domain, relieving intramolecular autoinhibition of p300. mTORC1-dependent p300 phosphorylation suppresses starvation-induced autophagy and activates lipogenesis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, domain interaction mapping, functional autophagy and lipogenesis assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay, domain-level mechanism established, functional cellular phenotypes, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29033323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p300 functions as a lysine 2-hydroxyisobutyryltransferase (Khib writer), targeting distinct sites from its acetylation targets. p300-catalyzed Khib on glycolytic enzymes (e.g., ENO1) regulates their catalytic activity; p300 deletion reduces Khib on these enzymes, impairs glycolysis, and sensitizes cells to glucose deprivation-induced death.\",\n      \"method\": \"In vitro enzymatic assay, quantitative proteomics (SILAC), mass spectrometry, genetic deletion (p300 KO cells), metabolic activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemistry, proteome-wide site mapping, KO with defined metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29775581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Transcription factor dimerization (IRF3, STAT1) activates p300 by enabling trans-autoacetylation of p300's autoinhibitory lysine-rich loop. A crystal structure of p300 shows the autoinhibitory loop invading the active site of a neighboring HAT domain, capturing a trans-autoacetylation intermediate. The RING domain also has an autoinhibitory role requiring rearrangement for substrate access.\",\n      \"method\": \"Crystal structure, in vitro HAT assay, mutagenesis, transcription factor dimerization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus mutagenesis in one study\",\n      \"pmids\": [\"30323286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DYRK1A physically interacts with p300 and CBP; overexpression of DYRK1A causes hyperphosphorylation of p300/CBP. ChIP-seq shows DYRK1A co-localizes with p300/CBP at enhancers; DYRK1A knockdown reduces H3K27ac at these enhancers, indicating DYRK1A modulates p300/CBP acetyltransferase activity at enhancers.\",\n      \"method\": \"Proteomics (mass spectrometry), co-immunoprecipitation, ChIP-seq, shRNA knockdown with H3K27ac readout\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interaction, ChIP-seq, functional knockdown, single lab\",\n      \"pmids\": [\"30137413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EP300 controls enhancer acetylation by interacting with TFAP2β, a lineage-defining transcription factor in MYCN-amplified neuroblastoma. EP300 (but not CBP) is essential for H3K27ac at core regulatory circuitry enhancers; PROTAC-mediated degradation of EP300 (JQAD1) causes loss of H3K27ac at these enhancers and rapid apoptosis in a CRBN-dependent manner.\",\n      \"method\": \"CRISPR KO, PROTAC degrader, ChIP-seq, co-immunoprecipitation, in vivo xenograft\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, chemical degrader, ChIP-seq, Co-IP, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"34772733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AFF1 (a super elongation complex subunit) is site-specifically acetylated by p300; this acetylation reduces AFF1 interaction with other SEC components and impairs P-TEFb-mediated RNA Pol II CTD phosphorylation both in vitro and in vivo. Upon genotoxic stress, p300-mediated AFF1 acetylation correlates with global transcriptional downregulation, and acetylation-defective AFF1 rescues transcription.\",\n      \"method\": \"In vitro acetylation and P-TEFb kinase assays, co-immunoprecipitation, mutagenesis, ChIP, genotoxic stress experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, mutagenesis rescue, in vivo correlation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31611376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"p300 physically interacts with NRF2 and interferes with NRF2-KEAP1 complex formation, thereby increasing NRF2 protein stability and promoting its nuclear localization. The acetyltransferase activity of p300 is indispensable for these stabilizing effects.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, nuclear fractionation, HAT-dead mutant analysis, cell viability assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, fractionation, enzymatic mutant, single lab\",\n      \"pmids\": [\"32057361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Short-chain fatty acids propionate and butyrate (but not acetate) activate p300 acetyltransferase by being converted to acyl-CoAs that are used by p300 to catalyze auto-acylation of the autoinhibitory loop, resulting in enzyme activation and global histone acetylation—distinct from HDAC inhibition.\",\n      \"method\": \"Quantitative proteomics of histone modifications, in vitro HAT assay, metabolite tracing, genetic/chemical perturbation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical mechanism, quantitative proteomics, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"34677127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures reveal that p300/CBP recognizes histone H4 N-terminal tail acetylation via its bromodomain (and contacts DNA minor grooves outside the pocket), directing the catalytic center to non-H4 histone tails within the same nucleosome. The primary write target after reading H4NTac is H2BNT; H2BNTac promotes H2A-H2B dissociation from the nucleosome.\",\n      \"method\": \"Cryo-EM structure, in vitro acetyltransferase assay, nucleosome dissociation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with in vitro functional validation, multiple readouts\",\n      \"pmids\": [\"37460559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The TAZ2 domain of p300 has an autoinhibitory function for HAT activity. Truncation of TAZ2 leads to hyperactive HAT and elevated H3K27ac and H3K18ac. Mechanistically, TAZ2 cooperates with neighboring HAT domains to maintain the active site in a 'closed' state; binding of transcription factors to TAZ2 or TAZ2 truncation induces a conformational opening of the active site.\",\n      \"method\": \"HAT activity assay, domain truncation mutagenesis, ChIP-seq, structural modeling, cancer mutation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic assay with mutagenesis, structural mechanism, ChIP-seq, single lab multiple orthogonal methods\",\n      \"pmids\": [\"37660055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUT (in the BRD4-NUT oncoprotein) contains an acidic transcriptional activation domain that binds the TAZ2 domain of p300, allosterically activating p300. NUT-TAZ2 interaction or cancer mutations interfering with TAZ2 autoinhibition activate p300, leading to a self-organizing, acetylation-dependent feed-forward reaction enabling long-range chromatin interactions via bromodomain multivalent acetyl-lysine binding.\",\n      \"method\": \"NMR structure, in vitro acetyltransferase assay, mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure, in vitro mechanism, mutagenesis, single lab multiple orthogonal methods\",\n      \"pmids\": [\"36522330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EP300 acetylates HSPA5 (GRP78) at K353, and this acetylation reduces HSPA5's ability to inhibit lipid peroxidation, thereby promoting ferroptosis. HDAC6 limits HSPA5 acetylation and subsequent ferroptosis. Genetic or pharmacological inhibition of EP300 increases PDAC cell resistance to ferroptosis.\",\n      \"method\": \"Acetylation site mapping, mutagenesis (K353 site), genetic and pharmacological inhibition, ferroptosis assays, co-immunoprecipitation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site mutagenesis, genetic/pharmacological loss-of-function with defined phenotype, single lab\",\n      \"pmids\": [\"37696842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p300 functions as a writer of histone crotonylation during preimplantation embryo development. P300 depletion causes developmental defects and transcriptome dysregulation. H3K18 crotonylation (H3K18cr), catalyzed by P300, localizes to active promoter regions and activates gene transcription required for embryo development.\",\n      \"method\": \"Genetic depletion (microinjection), RNA-seq, ChIP-seq, in vitro crotonylation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, genetic depletion with transcriptome and epigenome readouts, multiple orthogonal methods\",\n      \"pmids\": [\"39080296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"p300 is an obligate integrator of combinatorial transcription factor inputs for chromatin binding: systematic mutagenesis of all annotated p300 domains in live cells shows that chromatin association depends entirely on combinatorial binding through multiple TF-interaction domains. p300 acetyltransferase activity opposes its chromatin association, and N-terminal TF-interaction domains regulate catalytic activity.\",\n      \"method\": \"Single-molecule tracking (live cell imaging), domain mutagenesis, U2OS cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — single-molecule live imaging with systematic domain mutagenesis covering all annotated domains, multiple orthogonal findings in one study\",\n      \"pmids\": [\"38159566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC8 deacetylates EP300, causing its enzymatic inactivation. This inactivation increases EP300 binding to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites, altering chromatin accessibility and driving a neural crest-stem cell transcriptional state promoting melanoma brain metastasis.\",\n      \"method\": \"ATAC-seq, ChIP-seq, HDAC8 inhibitor treatment, loss-of-function, mass spectrometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and ATAC-seq with HDAC8 manipulation, functional phenotype in vivo, single lab\",\n      \"pmids\": [\"38030596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EP300 acetylates raptor (mTORC1 component), and nucleus-cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Nutrient deprivation causes AMPK-dependent phosphorylation of p300 at serine 89, promoting its cytoplasm-to-nucleus relocalization, reducing raptor acetylation and mTORC1 activity, and activating autophagy. Nutrient repletion causes PP2A-dependent dephosphorylation of nuclear p300, enabling CRM1-dependent nuclear export and mTORC1 reactivation. In Hutchinson-Gilford progeria syndrome, progerin mislocalizes p300 to the cytoplasm, hyperactivating mTORC1.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, siRNA knockdown, AMPK inhibition, CRM1 inhibition, in vivo mouse tissue analysis, patient cell lines\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — fractionation, Co-IP, multiple kinase/phosphatase manipulations, in vivo validation across tissues, disease model, multiple labs' concepts integrated\",\n      \"pmids\": [\"38267537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p300 functions as a succinylation writer (succinyl-CoA transferase) for cytoplasmic proteins including glycolytic enzymes. EP300 deletion leads to systemic reduction of lysine succinylation; p300-mediated succinylation of PGK1 promotes glycolysis, and mutation of the succinylated site of PGK1 impairs glycolysis and lactate production in lung cancer cells.\",\n      \"method\": \"Succinylome proteomics (SILAC/MS), CRISPR KO of EP300, site mutagenesis, glycolysis/metabolomics assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteome-wide succinylome, genetic KO, site mutagenesis with functional metabolic readout, single lab\",\n      \"pmids\": [\"38256128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EP300 acetylates FOXO3, and this acetylation promotes lapatinib sensitivity in HER2-positive breast cancer cells. Ectopic expression of wild-type but not acetylation-deficient EP300 increases acetylated-FOXO3 and lapatinib cytotoxicity; SIRT1/6 deacetylate FOXO3, counteracting EP300 activity.\",\n      \"method\": \"Ectopic expression, acetylation-deficient mutant, SIRT1/6 siRNA/inhibitor, drug sensitivity assay, ChIP\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus functional rescue, Co-IP, ChIP, single lab\",\n      \"pmids\": [\"31357743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p300 catalyzes acetylation of NONO at K198, stabilizing NONO by antagonizing its RNF8-mediated ubiquitination/degradation. NONO stabilizes CRAF and ARAF, reactivating pERK1/2 and promoting BRAF inhibitor resistance in melanoma. ERK1/2 activation feeds back to induce p300, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis, ubiquitination assay, in vitro/in vivo drug resistance assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro acetylation, mutagenesis, functional phenotype in vitro and in vivo, single lab\",\n      \"pmids\": [\"34017080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"p300/CBP sustains Polycomb-group protein occupancy at repressive sites by non-enzymatic functions: CBP stabilizes RNA Pol II at PcG-bound sites and promotes Pol II pausing independently of HAT activity. CBP/Pol II pausing is required for R-loop formation and nucleosome depletion at Polycomb Response Elements.\",\n      \"method\": \"ChIP-seq, genetic manipulation in Drosophila and mouse cells, HAT-dead mutant, R-loop detection\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, HAT-dead mutant, two organism systems, single lab\",\n      \"pmids\": [\"36206738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EP300 interacts with YAP and ZEB (via its Bromo domain and CBP/p300-HAT domain respectively) and simultaneously binds these factors to induce H3K27 acetylation at the LPCAT3 promoter, activating LPCAT3 transcription and thereby promoting ferroptosis sensitivity in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-qPCR, dual-luciferase reporter, xenograft model, domain interaction mapping\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter with domain mapping, in vivo validation, single lab\",\n      \"pmids\": [\"37166352\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EP300/p300 is a multifunctional lysine acetyltransferase (HAT/KAT3B) that acetylates histones (H3K27, H3K18, H4, H2B) and diverse non-histone substrates (p53, MyoD, FOXO3, AFF1, HSPA5, TP2, raptor, NONO) using multiple acyl-CoA donors (acetyl-, crotonyl-, 2-hydroxyisobutyryl-, succinyl-CoA), and whose catalytic activity is regulated by autoinhibitory intramolecular interactions (RING domain, TAZ2 domain, autoinhibitory lysine-rich loop) that are relieved by trans-autoacetylation triggered by dimerized transcription factors, by mTORC1-mediated phosphorylation, by AMPK-mediated phosphorylation at S89 (which also controls nucleocytoplasmic shuttling to regulate mTORC1 and autophagy), and by PKC-mediated phosphorylation at S89 (repressive); p300 acts as a scaffold bridging sequence-specific transcription factors (p53, Sox9, AR, NRF2, IRF3, STAT1, TFAP2β) to the basal transcription machinery (TBP), and as a cytoplasmic E4 ubiquitin ligase for p53 degradation—functions compartmentalized from its nuclear co-activator roles.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EP300/p300 is a multifunctional lysine acyltransferase that writes activating chromatin marks and acts as a transcriptional adaptor bridging sequence-specific transcription factors to the basal machinery, where it was first identified as a TBP-associated component [#0] and a direct p53-binding co-activator controlling cell-cycle checkpoint and apoptotic programs [#1]. Beyond histones (H3K27, H3K18, H2B), p300 acetylates a broad non-histone substrate set—MyoD [#2], transition protein TP2 [#10], the elongation factor AFF1 [#20], NRF2 [#21], NONO [#33], FOXO3 [#32], HSPA5 [#26] and the mTORC1 component raptor [#30]—coupling these modifications to muscle differentiation, chromatin condensation, transcriptional elongation, redox signaling, drug resistance and ferroptosis. Cryo-EM shows that p300 reads pre-existing H4 N-terminal acetylation through its bromodomain and directs catalysis to H2B tails to drive H2A-H2B eviction within the same nucleosome [#23], and it potentiates transcription specifically on chromatinized templates [#7]. It also functions as a promiscuous acyltransferase, installing crotonylation [#13, #27], 2-hydroxyisobutyrylation [#16] and succinylation [#31] on histones and cytoplasmic glycolytic enzymes, linking acyl-CoA metabolism to gene expression and metabolic flux. p300 catalytic activity is held in check by intramolecular autoinhibition involving an autoinhibitory lysine-rich loop, the RING domain and the TAZ2 domain [#17, #24, #25]; this brake is relieved by transcription-factor-dimerization-driven trans-autoacetylation [#17], by metabolite-derived acyl-CoAs that auto-acylate the loop [#22], and by mTORC1 phosphorylation that prevents HAT-RING contact [#15]. Chromatin engagement is itself dictated by combinatorial transcription-factor inputs, with acetyltransferase activity opposing stable chromatin association [#28]. A spatially distinct cytoplasmic pool acts as an E3/E4 polyubiquitin ligase for p53 [#9], and AMPK/PP2A-controlled phosphorylation at Ser89 governs nucleocytoplasmic shuttling that tunes raptor acetylation, mTORC1 activity and autophagy [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established p300 as a physical component of the basal transcription apparatus, providing the first mechanistic anchor for its co-activator role.\",\n      \"evidence\": \"Co-immunoprecipitation with TBP and proteolytic peptide mapping\",\n      \"pmids\": [\"8502484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the functional consequence of the TBP interaction\", \"Shared phosphoproteins (64/59 kDa) left unidentified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed p300 directly binds p53 and serves as a transcriptional adaptor controlling growth arrest and apoptosis, connecting it to tumor suppressor signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, co-localization, and p21/bax promoter and cell-cycle/apoptosis assays\",\n      \"pmids\": [\"9194565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether acetylation or scaffolding drives the effect\", \"No structural basis for the interaction\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that p300 acetylation of a non-histone substrate (MyoD) can directly activate that factor, broadening its enzymatic role beyond chromatin.\",\n      \"evidence\": \"In vitro acetylation, microinjection functional assay, acetylation-site mutagenesis\",\n      \"pmids\": [\"10944526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro acetylation site relevance in vivo not fully mapped\", \"Did not address chromatin context at the muscle promoter\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the first regulatory inputs onto p300—PKC phosphorylation at S89 (repressive) and the EID-1 HAT inhibitor—revealing that p300 activity is signal-controlled.\",\n      \"evidence\": \"In vivo phospho-site mapping plus kinase/reporter assays; yeast two-hybrid plus HAT inhibition assay\",\n      \"pmids\": [\"11020388\", \"11073990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of S89 phosphorylation effect not defined\", \"EID-1 inhibition mechanism on the HAT domain unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that p300 co-activation requires a nucleosomal template, linking its function mechanistically to histone hyperacetylation rather than naked-DNA transcription.\",\n      \"evidence\": \"Reconstituted in vitro transcription on chromatinized templates with Sox9 and ChIP\",\n      \"pmids\": [\"16109717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific histone residues responsible not pinned down here\", \"Generalizability beyond the collagen enhancer untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a compartment-specific moonlighting function: cytoplasmic p300/CBP act as an E4 polyubiquitin ligase that degrades p53, separating nuclear co-activation from cytoplasmic destruction.\",\n      \"evidence\": \"Subcellular fractionation, in vitro ubiquitination, domain mapping, p300/CBP-deficient cells\",\n      \"pmids\": [\"19805293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism of E4 activity within the N-terminal region not structurally defined\", \"Regulation switching between HAT and ligase roles unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the non-histone substrate repertoire and showed acetylation can disable a substrate's biophysical function, with TP2 acetylation reducing DNA condensation.\",\n      \"evidence\": \"In vitro acetylation, MS site mapping, CD and AFM, in vivo acetylation\",\n      \"pmids\": [\"19710011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of TP2 acetylation during spermiogenesis not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a selective small-molecule (plumbagin) inhibitor and identified K1358 as critical for inhibitor binding, supporting the HAT domain as a druggable target.\",\n      \"evidence\": \"In vitro HAT assay, in vivo p53 acetylation, docking, site-directed mutagenesis\",\n      \"pmids\": [\"19570987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over other acyltransferases in cells incomplete\", \"Non-competitive mechanism not crystallographically resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined BAG6 as a controller of p300 nucleocytoplasmic distribution coupling p300 localization to autophagy regulation via differential substrate acetylation.\",\n      \"evidence\": \"Fractionation, Co-IP, knockout MEFs, acetylation and autophagy assays\",\n      \"pmids\": [\"24852146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of BAG6-driven import not structurally defined\", \"Relationship to later AMPK/S89 shuttling model not integrated here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed p300 is a crotonyltransferase whose activity is governed by cellular acyl-CoA levels, establishing it as a metabolic sensor that converts metabolite flux into transcriptional output.\",\n      \"evidence\": \"In vitro enzymatic assay, cell-based transcription, crotonyl-CoA perturbation, ChIP\",\n      \"pmids\": [\"25818647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genomic distribution of crotonylation versus acetylation not fully mapped here\", \"Selectivity determinants for acyl-CoA choice unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified DDX24 as a negative regulator that blocks the p300-p53 interaction, adding to the network controlling p53 acetylation and senescence.\",\n      \"evidence\": \"Co-IP, RNAi, in vivo acetylation, p53 target expression\",\n      \"pmids\": [\"25867071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect competition for p53 binding not distinguished\", \"Single-lab finding without reciprocal structural data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a direct mTORC1-to-p300 phosphorylation axis that relieves intramolecular HAT-RING autoinhibition, linking nutrient signaling to p300 activation, autophagy suppression and lipogenesis.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, domain-interaction mapping, autophagy/lipogenesis assays\",\n      \"pmids\": [\"29033323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-site to conformational change link inferred, not structurally captured\", \"Crosstalk with other autoinhibitory domains not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Captured the structural basis of p300 autoactivation: transcription-factor dimerization triggers trans-autoacetylation of an autoinhibitory loop that invades a neighboring active site.\",\n      \"evidence\": \"Crystal structure, in vitro HAT assay, mutagenesis, TF dimerization assays\",\n      \"pmids\": [\"30323286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo kinetics of the trans-autoacetylation reaction not quantified\", \"RING-domain rearrangement mechanism only partially defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovered p300 as a 2-hydroxyisobutyryltransferase acting on glycolytic enzymes, directly coupling its enzymatic activity to metabolic flux and glucose-deprivation survival.\",\n      \"evidence\": \"In vitro assay, SILAC proteomics, MS, p300 KO cells, metabolic assays\",\n      \"pmids\": [\"29775581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and reversibility of cytoplasmic Khib not defined\", \"Site selectivity rules across substrates unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated DYRK1A as a kinase modulating p300/CBP enhancer activity, adding an enhancer-localized phospho-regulatory input to the network.\",\n      \"evidence\": \"MS interaction, Co-IP, ChIP-seq, shRNA with H3K27ac readout\",\n      \"pmids\": [\"30137413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation sites on p300 not mapped\", \"Causality between phosphorylation and activity not biochemically isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a non-redundant, druggable role for EP300 (over CBP) in sustaining core regulatory enhancers, validated by selective PROTAC degradation causing enhancer collapse and apoptosis.\",\n      \"evidence\": \"CRISPR KO, JQAD1 PROTAC, ChIP-seq, Co-IP, xenograft\",\n      \"pmids\": [\"34772733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of EP300 vs CBP specificity at these enhancers unresolved\", \"Generalizability beyond MYCN-amplified neuroblastoma untested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed p300 acetylation of AFF1 dampens super-elongation-complex assembly and P-TEFb-dependent Pol II CTD phosphorylation, revealing a repressive role in transcriptional elongation under genotoxic stress.\",\n      \"evidence\": \"In vitro acetylation and P-TEFb kinase assays, mutagenesis rescue, ChIP\",\n      \"pmids\": [\"31611376\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide scope of stress-induced AFF1 acetylation not mapped\", \"Interplay with p300's activating chromatin functions unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected p300 acetylation to drug-response phenotypes, with FOXO3 acetylation promoting lapatinib sensitivity and NONO acetylation driving BRAF-inhibitor resistance via a p300-ERK feedback loop.\",\n      \"evidence\": \"Acetylation-deficient mutants, SIRT manipulation, ubiquitination assays, drug-sensitivity and in vivo resistance assays\",\n      \"pmids\": [\"31357743\", \"34017080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of opposing drug-response outcomes not reconciled\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed p300 stabilizes NRF2 by disrupting NRF2-KEAP1 complex formation in a HAT-dependent manner, linking p300 to oxidative-stress transcriptional responses.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, fractionation, HAT-dead mutant\",\n      \"pmids\": [\"32057361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NRF2 acetylation site(s) not mapped\", \"Direct versus indirect KEAP1 interference not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that short-chain fatty acid-derived acyl-CoAs activate p300 by auto-acylating its autoinhibitory loop, mechanistically distinct from HDAC inhibition.\",\n      \"evidence\": \"Histone-modification proteomics, in vitro HAT assay, metabolite tracing, genetic/chemical perturbation\",\n      \"pmids\": [\"34677127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution to histone acetylation versus HDAC inhibition in vivo not fully partitioned\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how p300 reads and writes within a nucleosome: bromodomain recognition of H4 N-terminal acetylation directs catalysis to H2B tails, promoting H2A-H2B eviction.\",\n      \"evidence\": \"Cryo-EM structure, in vitro acetylation, nucleosome dissociation assay\",\n      \"pmids\": [\"37460559\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of the initiating H4 acetylation not defined\", \"Functional impact on transcription in cells not directly tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the TAZ2 domain as a second autoinhibitory module whose conformational opening by transcription-factor binding (including oncogenic NUT) activates the HAT, unifying autoinhibition with feed-forward chromatin activation.\",\n      \"evidence\": \"HAT assays, domain truncation, ChIP-seq, NMR structure, cancer-mutation analysis\",\n      \"pmids\": [\"37660055\", \"36522330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative interplay among RING, loop, and TAZ2 autoinhibition not integrated\", \"How cancer mutations map onto each brake incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a non-enzymatic role for p300/CBP in sustaining Polycomb repression via Pol II pausing and R-loop formation, showing its function is not solely acetyltransferase-dependent.\",\n      \"evidence\": \"ChIP-seq, HAT-dead mutant, Drosophila and mouse cells, R-loop detection\",\n      \"pmids\": [\"36206738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of HAT-independent Pol II stabilization unknown\", \"Direct versus indirect contribution to PcG occupancy unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that p300 chromatin association is dictated by combinatorial transcription-factor inputs and is opposed by its own catalytic activity, reframing how p300 is recruited genome-wide.\",\n      \"evidence\": \"Single-molecule tracking, systematic domain mutagenesis, U2OS cells\",\n      \"pmids\": [\"38159566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the dominant TF combinations at specific loci not enumerated\", \"Mechanism by which acetylation reduces chromatin dwell-time unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined deacetylase-mediated control of p300 output, with HDAC8 inactivating EP300 to redirect its TF-site occupancy and HDAC6/SIRT counter-regulating substrate acetylation in disease contexts.\",\n      \"evidence\": \"ATAC-seq, ChIP-seq, MS, HDAC inhibitor/loss-of-function, in vivo metastasis models\",\n      \"pmids\": [\"38030596\", \"37696842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Autoacetylation sites removed by HDAC8 not fully mapped\", \"Generalizability beyond melanoma/PDAC contexts untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established p300 as a writer of histone crotonylation (H3K18cr) essential for preimplantation embryo development, demonstrating developmental requirement for its acyltransferase function.\",\n      \"evidence\": \"Genetic depletion, RNA-seq, ChIP-seq, in vitro crotonylation assay\",\n      \"pmids\": [\"39080296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative developmental contribution of crotonylation versus acetylation not partitioned\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked p300 acetylation to ferroptosis through HSPA5-K353 acetylation and YAP/ZEB-dependent LPCAT3 enhancer activation, connecting p300 to lipid-peroxidation cell-death control.\",\n      \"evidence\": \"Site mapping/mutagenesis, Co-IP, ChIP, luciferase reporter, ferroptosis assays, xenograft\",\n      \"pmids\": [\"37696842\", \"37166352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of pro- versus anti-ferroptotic outcomes not reconciled\", \"Single-lab findings per substrate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated p300 localization into nutrient signaling: AMPK-dependent S89 phosphorylation drives nuclear entry that reduces raptor acetylation and mTORC1 activity to activate autophagy, with PP2A/CRM1 reversing the cycle, and progerin-driven mislocalization implicating the axis in Hutchinson-Gilford progeria.\",\n      \"evidence\": \"Fractionation, Co-IP, kinase/phosphatase and CRM1 manipulations, mouse tissue, patient cells\",\n      \"pmids\": [\"38267537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of S89-dependent shuttling not defined\", \"Reconciliation with earlier PKC-S89 repressive model not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed p300 functions as a succinyltransferase on cytoplasmic glycolytic enzymes (PGK1), establishing succinylation as another metabolic-regulatory output of p300 in cancer.\",\n      \"evidence\": \"Succinylome proteomics, CRISPR KO, site mutagenesis, glycolysis/metabolomics\",\n      \"pmids\": [\"38256128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoplasmic substrate selectivity rules undefined\", \"Reversibility/desuccinylase counterpart not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple autoinhibitory brakes (lysine-rich loop, RING, TAZ2), diverse acyl-CoA selectivity, compartment-specific catalytic versus ligase functions, and combinatorial TF-driven recruitment are coordinated into a single integrated regulatory logic remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking acyl-CoA choice to substrate/site selection\", \"Switch governing nuclear HAT versus cytoplasmic E4 ligase roles undefined\", \"Quantitative hierarchy among the three autoinhibitory domains unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 10, 20, 21, 26, 32, 33]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [13, 16, 22, 27, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [23, 7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 7, 17, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 12, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9, 12, 16, 30, 31]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7, 23, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7, 17, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13, 23, 24, 27, 34]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 15, 30]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 26, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 21, 30, 33]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"TBP\", \"MYOD1\", \"AFF1\", \"NRF2\", \"NONO\", \"TFAP2B\", \"RPTOR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}