{"gene":"EP400","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2001,"finding":"EP400 (p400) is a SWI2/SNF2-related 400 kDa ATPase that forms a large chromatin-remodeling complex with TRRAP/PAF400, DNA helicases TAP54alpha/beta, actin-like proteins, and the human Enhancer of Polycomb homolog. E1A binds this complex, and an E1A mutant defective in p400 binding is also defective in transformation, establishing p400 complex formation as essential for E1A-mediated transformation.","method":"Co-immunoprecipitation, mass spectrometry identification of complex components, E1A deletion mutant analysis, partial rescue with p400 fragments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mutant rescue experiments, multiple orthogonal methods in a focused mechanistic study","pmids":["11509179"],"is_preprint":false},{"year":2005,"finding":"p400 is a component of the p53→p21 senescence pathway: acute shRNA depletion of p400 causes premature senescence in human fibroblasts (G1 arrest, p21 induction, SAHF, beta-gal staining), and these phenotypes are rescued by co-expression of p53-shRNA or p21-shRNA. p400 complex co-localizes with p53 on the p21 promoter, indicating p400 inhibits p53→p21 transcription.","method":"shRNA knockdown, co-immunoprecipitation/ChIP showing p400 at p21 promoter, genetic epistasis via co-depletion of p53/p21","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis by double knockdown with defined phenotypic rescue, ChIP localization, multiple orthogonal methods","pmids":["15655109"],"is_preprint":false},{"year":2005,"finding":"p400 is required for E1A-induced apoptosis: E1A increases p400 expression and promotes co-association of p400-TRRAP with Rb; suppression of p400 by stable RNAi reduces ARF, p53 levels, and apoptosis in E1A-expressing cells. p400 is identified as a regulator of the ARF-p53 pathway.","method":"Stable RNAi knockdown, measurement of ARF/p53/apoptosis levels, co-immunoprecipitation of p400-TRRAP-Rb","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined apoptosis phenotype and pathway placement, single lab","pmids":["15741165"],"is_preprint":false},{"year":2006,"finding":"Tip60 and p400 (within the same complex) play antagonistic roles: p400 represses p21 expression in unstressed cells (allowing cell cycle progression), while Tip60 activates p53 target proapoptotic genes. p400 inhibits Tip60 function in the absence of DNA damage, and this inhibition is abolished after DNA damage. Both are required for UV-induced apoptosis.","method":"siRNA knockdown of p400 and Tip60 separately, measurement of p21 expression, cell cycle analysis, apoptosis assays, functional epistasis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with multiple phenotypic readouts, single lab, two orthogonal methods","pmids":["16601686"],"is_preprint":false},{"year":2008,"finding":"VHL loss-induced senescence requires p400 (and Rb): acute VHL inactivation causes a senescent-like phenotype that is independent of p53 and HIF but dependent on Rb and the SWI2/SNF2 chromatin remodeler p400, placing p400 downstream of VHL in a tumor-suppressive senescence pathway.","method":"Genetic epistasis using shRNA against p400 and Rb in VHL-inactivated cells, in vitro and in vivo senescence assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by double knockdown, in vivo confirmation, single lab","pmids":["18297059"],"is_preprint":false},{"year":2008,"finding":"In embryonic stem cells, p400 localization to promoters of both silent and active genes depends on H3K4me3, and Nanog depletion reduces p400 binding to target promoters without affecting H3K4me3 levels, indicating Tip60-p400 integrates Nanog and H3K4me3 signals to regulate ESC gene expression.","method":"RNAi screen, ChIP for p400 at promoters, Nanog knockdown epistasis, gene expression profiling","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-based localization, genetic epistasis with Nanog, multiple orthogonal methods, published in high-impact journal","pmids":["18614019"],"is_preprint":false},{"year":2008,"finding":"E1A targets p400 to stabilize and upregulate the oncoprotein Myc: E1A promotes coassociation of Myc and p400 at Myc target genes, leading to transcriptional induction. Forced Myc expression rescues activity of an E1A mutant defective in p400 binding, establishing Myc as the downstream target of the E1A-p400 interaction.","method":"Co-immunoprecipitation, ChIP at Myc target genes, RNAi, rescue with Myc overexpression, E1A p400-binding mutant analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and genetic rescue, single lab","pmids":["18413597"],"is_preprint":false},{"year":2010,"finding":"p400 ATPase activity and Tip60 acetyltransferase cooperate during DNA double-strand break (DSB) repair: p400 is recruited to DSBs by a mechanism independent of ATM but requiring Mdc1. p400 ATPase activity destabilizes nucleosomes in gamma-H2AX domains surrounding DSBs, which is required for RNF8-dependent chromatin ubiquitination and subsequent recruitment of BRCA1 and 53BP1.","method":"Chromatin fractionation, ATPase-dead mutant analysis, siRNA knockdown, recruitment assays for BRCA1/53BP1, ubiquitination assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ATPase-dead mutagenesis combined with multiple downstream readouts (nucleosome destabilization, ubiquitination, factor recruitment), multiple orthogonal methods","pmids":["20876283"],"is_preprint":false},{"year":2010,"finding":"p400 is required for correct control of ROS metabolism: p400 depletion increases intracellular ROS levels and causes DNA damage. The effects of p400 on cell cycle progression, apoptosis, and senescence are dependent on ATM-dependent DDR pathways and involve direct transcriptional regulation of specific promoters including those controlling ROS metabolism.","method":"siRNA knockdown, ROS measurement, ATM siRNA epistasis, ChIP at specific promoters","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts with epistasis, ChIP validation, single lab","pmids":["20548951"],"is_preprint":false},{"year":2010,"finding":"p400/mDomino catalyzes ATP-dependent deposition of histone variant H2A.Z into nucleosomes to regulate gene expression, and is essential for adult bone marrow hematopoiesis and cell-cycle progression. Loss of p400/mDomino in MEFs causes S and G2/M phase defects, polyploidy, and multinucleation, with impaired expression of FoxM1 and c-Myc target cell-cycle genes.","method":"Conditional knockout mouse (Mx1-Cre), hematopoietic colony assay, cell-cycle FACS, DNA microarray, H2A.Z deposition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotypes, multiple orthogonal methods, in vivo and in vitro validation","pmids":["20610385"],"is_preprint":false},{"year":2012,"finding":"p400 ATPase is required for DNA repair by homologous recombination (HR): p400-depleted cells are defective in HR-dependent repair, Rad51 recruitment to DSBs, and homology-directed repair. p400 and Rad51 are found in the same complex and both promote chromatin remodeling (decompaction) around DSBs.","method":"Co-immunoprecipitation of p400-Rad51 complex, siRNA knockdown, Rad51 focus formation assay, HR reporter assay, chromatin remodeling assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP showing complex formation, multiple functional assays (HR reporter, Rad51 foci, chromatin decompaction), single lab with multiple orthogonal methods","pmids":["23266955"],"is_preprint":false},{"year":2012,"finding":"p400 deposits H2A.Z within the p21 promoter to repress p21 gene expression. During replicative senescence of IMR-90 fibroblasts, p400 levels decline and H2A.Z is lost from the p21 promoter, contributing to sustained p21 transcription and senescence onset.","method":"ChIP for H2A.Z and p400 at p21 promoter, nucleosome mapping, comparison between young and senescent cells","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — ChIP in multiple cell states with consistent findings, single lab, single method type","pmids":["23146670"],"is_preprint":false},{"year":2012,"finding":"The p400/Brd8 complex promotes adipogenesis by incorporating histone variant H2A.Z at PPARgamma target gene promoters; shRNA-mediated knockdown of Brd8 or H2A.Z abolishes 3T3-L1 preadipocyte differentiation and blocks accumulation of PPARgamma, p400, and RNA Pol II at PPARgamma target genes.","method":"shRNA knockdown, lipid accumulation assay, ChIP for p400/PPARgamma/H2A.Z/Pol II at target gene promoters","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined adipogenesis phenotype, ChIP validation of mechanism, single lab","pmids":["23064015"],"is_preprint":false},{"year":2013,"finding":"Hdac6 co-purifies with Tip60-p400 complex from embryonic stem cells and is required for Tip60-p400 binding to many of its target genes. Unlike differentiated cells where Hdac6 is cytoplasmic, Hdac6 is largely nuclear in ESCs and interacts with Tip60-p400. Hdac6 does not appear to deacetylate histones in this context but is necessary for robust ESC differentiation.","method":"Co-purification/co-IP, ChIP for Hdac6 and Tip60-p400 at target promoters, siRNA knockdown, cellular fractionation, differentiation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-purification establishing complex membership, ChIP showing co-localization, epistatic knockdown, localization by fractionation, multiple orthogonal methods","pmids":["24302573"],"is_preprint":false},{"year":2015,"finding":"EP400 deposits histone H3.3 into promoters and enhancers during gene activation alongside H2AZ. EP400 binds preferentially to acetylated H2AZ/H3.3-containing chromatin templates and is required for transcription stimulation by double-variant chromatin in vitro. EP400 efficiently exchanges H2A and H3.1 with H2AZ and H3.3, respectively, in a chromatin- and ATP-stimulated manner in vitro.","method":"Biochemical reconstitution of chromatin templates, in vitro transcription assay, histone exchange assay with recombinant histones, immobilized chromatin pulldown, ChIP-seq in vivo","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant histones and ATP dependence, in vitro transcription assay, in vivo ChIP-seq, multiple orthogonal methods","pmids":["26669263"],"is_preprint":false},{"year":2015,"finding":"p400 ATPase acts as a brake on alternative end-joining (alt-EJ) DNA repair: p400 depletion increases alt-EJ frequency, generates large deletions after DSB repair, and this increase is dependent on CtIP-mediated resection. p400 depletion also leads to PARP and DNA ligase 3 recruitment to DSBs, conferring sensitivity to PARP inhibitors.","method":"Intracellular reporter substrates for alt-EJ, siRNA knockdown, CtIP epistasis, PARP inhibitor sensitivity assay, immunofluorescence for PARP/ligase 3 recruitment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter-based assay with epistasis, multiple functional readouts, single lab","pmids":["26578561"],"is_preprint":false},{"year":2016,"finding":"ATM kinase physically interacts with p400 ATPase independently of DNA damage state via the N-terminal domain of p400. This interaction can be reconstituted in Sf9 insect cells without mammalian bridging proteins, and overexpression of ATM-interacting p400 N-terminal fragments acts as a dominant negative, inhibiting DNA damage repair and cell proliferation.","method":"Co-immunoprecipitation, heterologous reconstitution in Sf9 cells, dominant-negative overexpression, DNA repair and proliferation assays","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstituted interaction in Sf9 cells plus co-IP and dominant-negative functional validation, single lab","pmids":["27814680"],"is_preprint":false},{"year":2017,"finding":"Merkel cell polyomavirus Small T antigen binds MYCL and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. The ST-MYCL-EP400 complex binds together at specific gene promoters and activates their expression. MYCL and EP400 are required for maintenance of MCC cell viability and cooperate with ST to promote gene expression and cellular transformation.","method":"Large-scale immunoprecipitation with mass spectrometry, ChIP-seq, RNA-seq, CRISPR-Cas9 genome-wide screen, transformation assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — mass spec identification of complex, ChIP-seq confirming co-occupancy, CRISPR screen confirmation, multiple orthogonal methods","pmids":["29028833"],"is_preprint":false},{"year":2019,"finding":"Ep400 is required for oligodendrocyte terminal differentiation and myelination: Ep400-deficient oligodendrocyte precursors develop normally but fail to terminally differentiate. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene, and is required to induce Myrf, a central transcriptional regulator of myelination. Ep400 deletion in mature oligodendrocytes causes no phenotype, indicating Ep400 is dispensable for myelin maintenance.","method":"Conditional knockout mouse, ChIP for Ep400 at Myrf regulatory regions, co-immunoprecipitation of Ep400-Sox10, histological and myelin staining, immunofluorescence","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined myelination phenotype, co-IP, ChIP at target gene, multiple orthogonal methods, temporally controlled deletion","pmids":["31081019"],"is_preprint":false},{"year":2019,"finding":"Ep400 deletion in Schwann cells causes peripheral neuropathy through terminal differentiation defects. Mechanistically, Ep400 absence alters H2A.Z genomic distribution, causing H2A.Z to remain at promoters of early developmental regulators (Tfap2a, Pax3). Deletion of Tfap2a in Ep400-deficient Schwann cells provides partial rescue, indicating persistent expression of early regulators (maintained by Ep400 loss) mediates the defect.","method":"Conditional knockout mouse, ChIP-seq for H2A.Z distribution, genetic epistasis (double knockout with Tfap2a), histological analysis of peripheral nerves","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, genome-wide ChIP-seq, epistasis rescue via double KO, multiple orthogonal methods","pmids":["31142747"],"is_preprint":false},{"year":2021,"finding":"JAZF1 is a member of a p400 sub-complex containing MBTD1 (but excluding ANP32E), identified by mass spectrometry-based H2A variant chaperone complex characterization. JAZF1 depletion leads to reduced H2A.Z acetylation at >1000 regulatory sites without affecting H2A.Z nucleosome positioning, suggesting JAZF1 recruits TIP60 acetyltransferase activity to regulate H2A.Z acetylation.","method":"Mass spectrometry identification of complex composition, ChIP-seq for H2A.Z acetylation after JAZF1 depletion, RNA-seq","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex identification, ChIP-seq functional validation, single lab","pmids":["33445503"],"is_preprint":false},{"year":2021,"finding":"Phf5a stabilizes the p400 histone chaperone complex at immunoglobulin switch regions, which promotes deposition of H2A variants (H2AX and H2A.Z) critical for early DNA damage response and NHEJ, respectively, during class switch recombination. Depletion of Phf5a or p400 blocks repair of AID-induced and I-SceI-induced DNA DSBs.","method":"siRNA screen, ChIP for p400 at switch regions, H2A variant deposition assays, I-SceI reporter for DSB repair, flow cytometric CSR assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA-based functional screen, ChIP, DSB repair reporter, multiple orthogonal methods, single lab","pmids":["33938017"],"is_preprint":false},{"year":2023,"finding":"EP400/TIP60 remodeler compensates for loss of SWI/SNF activity by reestablishing chromatin accessibility at most gene promoters (but not enhancers) during prolonged SWI/SNF inhibition. EP400 and SWI/SNF show synthetic lethality in cancer cell lines. This places EP400 in a parallel chromatin accessibility pathway to SWI/SNF at promoters.","method":"Fast-acting SWI/SNF inhibitor treatment, ATAC-seq for chromatin accessibility, genetic epistasis with EP400 depletion, synthetic lethality in cancer cell lines","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical-genetic approach with fast-acting inhibitor, genome-wide ATAC-seq, synthetic lethality validation across cancer lines, multiple orthogonal methods","pmids":["37922899"],"is_preprint":false},{"year":2023,"finding":"Inactivation of Ep400 (or Kat5/Tip60) in cranial neural crest cells severely impairs carbohydrate and amino acid metabolism, decreases protein synthesis, proliferation, and survival of neural crest cells, leading to loss of most facial structures. Heterozygous Kat5 loss impairs palatogenesis, implicating the Tip60/Ep400 complex in facial morphogenesis.","method":"CRISPR/Cas9 genome editing and conditional mutagenesis in mouse, metabolic analysis, histology, immunofluorescence for proliferation/survival markers","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, metabolic and proliferation readouts, single lab","pmids":["37024457"],"is_preprint":false},{"year":2024,"finding":"EP400 deposits H3.3 into promoters of major zygotic genome activation (ZGA) genes in mouse oocytes and early embryos. EP400 forms a protein complex with NFYA at ZGA gene promoters, modulates H3.3 distribution between euchromatin and heterochromatin, promotes transcription elongation, and activates genes regulating mitochondrial functions and TCA cycle enzymes. Maternal Ep400 depletion causes developmental arrest at the 2-to-4-cell stage.","method":"Oocyte-specific conditional knockout, co-immunoprecipitation of EP400-NFYA, ChIP-seq for H3.3 distribution, RNA-seq, embryo developmental assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, co-IP of complex, ChIP-seq, RNA-seq, defined developmental phenotype, multiple orthogonal methods","pmids":["38493496"],"is_preprint":false},{"year":2024,"finding":"Adenovirus small e1a promotes derepression of Alu retrotransposons via physical interaction with EP400 chromatin remodeler at YAP/TEAD- and AP-1-bound enhancers; EP400 ablation abrogates e1a-induced Alu derepression. This establishes EP400 as required for e1a-mediated epigenomic changes at enhancer Alus.","method":"EP400 ChIP-seq, ATAC-seq/epigenome profiling, EP400 ablation by CRISPR, RNA-seq for Alu transcription, co-immunoprecipitation of e1a-EP400","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, co-IP, CRISPR ablation with functional readout, single lab","pmids":["39011896"],"is_preprint":false},{"year":2024,"finding":"EP400 suppresses melanoma cell growth via interaction with c-MYC: a LINC00944-encoded peptide disrupts the EP400-MYC interaction, reduces c-MYC protein expression, and represses MYC transcriptional activity including fatty acid and glucose metabolism target genes.","method":"Co-immunoprecipitation of EP400-MYC complex, peptide competition assay, MYC reporter/expression assays, cell proliferation assays","journal":"Biochemical pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP of EP400-MYC and competition assay, single lab, single method for complex disruption","pmids":["39586403"],"is_preprint":false},{"year":2025,"finding":"The p400 complex promotes HIV-1 latency by suppressing viral transcription: EP400 and its complex partner DMAP1 co-localize with paused RNA Polymerase II at transcriptional start sites, and their depletion markedly increases RNAPII pause release at the HIV-1 locus. EP400 depletion also increases expression of T-cell factors that activate HIV-1 transcription.","method":"shRNAmir pooled screen, ChIP-seq for EP400/DMAP1/RNAPII at HIV locus and cellular genes, HIV transcription reporter assays, primary CD4+ T cell assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, functional screen, primary cell validation, single lab","pmids":["40842241"],"is_preprint":false},{"year":2025,"finding":"EP400 ATPase (with DMAP1) restricts HIV-1 transcription in a Tat-dependent manner: EP400 associates with RNAPII C-terminal domain, while DMAP1 directly binds the viral transactivator Tat's basic domain, blocking Tat-TAR RNA interaction and limiting p-TEFb-mediated RNAPII Ser2 phosphorylation and elongation. Repression requires simultaneous interactions among EP400, DMAP1, and Tat.","method":"Co-immunoprecipitation of DMAP1-Tat, EP400-RNAPII interaction assays, ChIP-seq, Tat-deficient virus experiments, RNAPII Ser2 phosphorylation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein interaction mapped (DMAP1-Tat, EP400-RNAPII CTD), mechanistic epistasis with Tat-deficient virus, ChIP-seq, RNAPII modification readout, multiple orthogonal methods","pmids":["41414674"],"is_preprint":false},{"year":2025,"finding":"PRMT5 sustains the Tip60-EP400 complex in Merkel cell carcinoma via SRSF1: PRMT5-mediated modification of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper KAT5 (Tip60) splicing and Tip60-EP400 activity. PRMT5 inhibition disrupts SRSF1 recruitment, leading to splicing defects (exon skipping, intron retention) in KAT5 transcripts and impaired Tip60-EP400 complex activity.","method":"RNA-seq, Iso-Seq for alternative splicing analysis, PRMT5 inhibition, SRSF1 modification assays, complex activity assays in MCC cells","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Iso-Seq for splicing, RNA-seq, mechanistic connection between PRMT5/SRSF1/KAT5 splicing and EP400 complex integrity, single lab","pmids":["40846633"],"is_preprint":false},{"year":2025,"finding":"EP400 (within NuA4/TIP60) pre-acetylates H2A.Z to facilitate H2A.Zac-H2B dimer association with the complex before EP400-mediated incorporation into chromatin at gene promoters, positively regulating transcription. This establishes a coordinated mechanism where TIP60 acetyltransferase activity and EP400 remodeling activity are functionally coupled.","method":"EP400 rapid depletion system, functional genomics (ChIP-seq, ATAC-seq), biochemical analyses of H2A.Z acetylation and chromatin incorporation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — EP400 rapid depletion with genomic and biochemical readouts, multiple orthogonal methods; preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"EP400 is the catalytic ATPase subunit of the NuA4/TIP60 chromatin remodeling complex that drives ATP-dependent exchange of canonical histones for variants H2A.Z and H3.3 at gene promoters and enhancers; it cooperates with TIP60 acetyltransferase activity (which pre-acetylates H2A.Z before loading), recruits transcription factors (e.g., Nanog, Sox10, NFYA), regulates RNAPII pausing and elongation, promotes DNA repair by homologous recombination and NHEJ through nucleosome destabilization at DSBs, suppresses p53→p21 transcription to prevent premature senescence, and is essential for embryonic hematopoiesis, oligodendrocyte myelination, Schwann cell differentiation, ESC identity, and early embryonic zygotic genome activation."},"narrative":{"mechanistic_narrative":"EP400 (p400) is the SWI2/SNF2-related ATPase subunit of a large NuA4/TIP60 chromatin-remodeling complex that catalyzes ATP-dependent exchange of canonical histones for the variants H2A.Z and H3.3 at gene promoters and enhancers to control transcription [PMID:11509179, PMID:26669263]. EP400 efficiently swaps H2A and H3.1 for H2A.Z and H3.3 in a chromatin- and ATP-stimulated reaction, binds preferentially to acetylated H2A.Z/H3.3 templates, and its remodeling activity is functionally coupled to the TIP60 acetyltransferase, which pre-acetylates H2A.Z before incorporation [PMID:26669263]. Deposition of these variants directs context-specific gene programs: EP400 integrates Nanog and H3K4me3 signals at promoters to maintain embryonic stem cell identity [PMID:18614019, PMID:24302573], partners with Sox10 to induce Myrf during oligodendrocyte differentiation [PMID:31081019], controls H2A.Z distribution to silence early regulators (Tfap2a, Pax3) during Schwann cell maturation [PMID:31142747], cooperates with PPARgamma during adipogenesis [PMID:23064015], and forms a complex with NFYA to drive H3.3 deposition and transcription elongation at zygotic genome activation genes, with maternal depletion arresting embryos at the 2-to-4-cell stage [PMID:38493496]. Through H2A.Z deposition at the p21 promoter, EP400 represses the p53→p21 axis to permit cell-cycle progression and prevent premature senescence; its loss triggers p53/p21-dependent senescence and is required for the senescence response downstream of VHL [PMID:15655109, PMID:23146670, PMID:18297059]. EP400 ATPase activity also destabilizes nucleosomes around DNA double-strand breaks, a step required for RNF8-dependent ubiquitination and recruitment of BRCA1, 53BP1, and Rad51, thereby promoting homologous recombination and NHEJ while restraining mutagenic alternative end-joining [PMID:20876283, PMID:23266955, PMID:26578561]. EP400 functions in parallel to SWI/SNF in establishing promoter chromatin accessibility, producing synthetic lethality in cancer cells [PMID:37922899], and is exploited by viral oncoproteins—adenovirus E1A targets EP400 to upregulate Myc and drive transformation, and Merkel cell polyomavirus small T recruits MYCL to the EP400 complex to maintain carcinoma viability [PMID:11509179, PMID:18413597, PMID:29028833].","teleology":[{"year":2001,"claim":"Established EP400 as the ATPase core of a defined multi-subunit chromatin remodeling complex and linked that complex to viral oncogenic transformation, framing the biochemical identity of the protein.","evidence":"Co-IP and mass spectrometry of the complex plus E1A deletion-mutant transformation assays","pmids":["11509179"],"confidence":"High","gaps":["Catalytic substrate of the ATPase not yet defined","Histone variant exchange activity not yet demonstrated"]},{"year":2005,"claim":"Placed EP400 as a repressor of the p53→p21 senescence pathway, explaining why loss of this remodeler drives premature senescence.","evidence":"shRNA depletion in human fibroblasts with p53/p21 co-depletion rescue and ChIP at the p21 promoter","pmids":["15655109"],"confidence":"High","gaps":["Molecular mechanism of repression at p21 not yet defined (variant deposition shown later)","Whether repression is direct ATPase-dependent unresolved here"]},{"year":2006,"claim":"Showed EP400 and TIP60 within the same complex have antagonistic, DNA-damage-gated outputs, establishing a switch between proliferative repression and proapoptotic activation.","evidence":"Separate siRNA knockdown of p400 and Tip60 with p21, cell-cycle, and apoptosis readouts","pmids":["16601686"],"confidence":"Medium","gaps":["Biochemical basis of p400 inhibition of Tip60 not defined","Single lab"]},{"year":2008,"claim":"Connected EP400 to ESC identity by showing its promoter recruitment depends on H3K4me3 and Nanog, defining how the complex is targeted in pluripotent cells.","evidence":"RNAi screen, p400 ChIP at promoters, Nanog knockdown epistasis in ESCs","pmids":["18614019"],"confidence":"High","gaps":["Direct reader of H3K4me3 within the complex not identified","Functional consequence at individual target genes limited"]},{"year":2008,"claim":"Extended EP400's senescence role downstream of a distinct tumor-suppressor input (VHL) and to oncoprotein-driven apoptosis and Myc activation, broadening its tumor-suppressive and oncogenic context.","evidence":"shRNA epistasis in VHL-inactivated cells; stable RNAi with apoptosis/ARF readouts; co-IP and ChIP at Myc targets","pmids":["18297059","15741165","18413597"],"confidence":"Medium","gaps":["How one remodeler produces both pro- and anti-proliferative outputs not mechanistically unified","Single-lab contexts"]},{"year":2010,"claim":"Defined EP400's role in DNA double-strand break repair, showing its ATPase destabilizes nucleosomes in gamma-H2AX domains to license downstream ubiquitination and repair-factor recruitment.","evidence":"ATPase-dead mutant analysis, chromatin fractionation, BRCA1/53BP1 recruitment and ubiquitination assays","pmids":["20876283"],"confidence":"High","gaps":["Mechanism of Mdc1-dependent recruitment not fully mapped","Histone variant identity at DSBs not resolved here"]},{"year":2010,"claim":"Identified EP400 as the catalyst of H2A.Z deposition and tied this activity to hematopoiesis, cell-cycle gene control, and ROS metabolism in vivo.","evidence":"Conditional knockout mouse, H2A.Z deposition assays, cell-cycle FACS, microarray; ROS and ATM-epistasis assays","pmids":["20610385","20548951"],"confidence":"High","gaps":["Direct in vitro variant-exchange biochemistry not yet shown","Relationship of ROS phenotype to variant deposition unclear"]},{"year":2012,"claim":"Defined EP400 as a homologous recombination factor and a brake on mutagenic alternative end-joining, refining its role to specific DSB repair pathway choice.","evidence":"p400-Rad51 co-IP, HR and alt-EJ reporter assays, CtIP epistasis, PARP inhibitor sensitivity, chromatin decompaction assays","pmids":["23266955","26578561"],"confidence":"Medium","gaps":["How EP400 biases pathway choice mechanistically not fully resolved","alt-EJ findings single lab"]},{"year":2012,"claim":"Mechanistically linked EP400-driven H2A.Z deposition at the p21 promoter to senescence onset and to lineage-specific gene activation in adipogenesis, generalizing variant deposition as the effector mechanism.","evidence":"ChIP for H2A.Z/p400 at p21 in young vs senescent cells; Brd8/H2A.Z knockdown and ChIP at PPARgamma targets in 3T3-L1","pmids":["23146670","23064015"],"confidence":"Medium","gaps":["Causality between H2A.Z loss and senescence vs correlation not fully disentangled","Single-method ChIP studies"]},{"year":2013,"claim":"Revealed Hdac6 as an unexpected nuclear partner required for Tip60-p400 target binding in ESCs, expanding the complex's composition in pluripotent cells.","evidence":"Co-purification, ChIP co-localization, fractionation, and differentiation assays in ESCs","pmids":["24302573"],"confidence":"High","gaps":["Catalytic role of Hdac6 in this context excluded but its mechanistic contribution unclear","How Hdac6 promotes complex recruitment unknown"]},{"year":2015,"claim":"Provided the definitive biochemical demonstration that EP400 exchanges both H2A.Z and H3.3 into chromatin in an ATP-stimulated manner and that double-variant chromatin stimulates transcription.","evidence":"In vitro reconstitution with recombinant histones, in vitro transcription, immobilized chromatin pulldown, and ChIP-seq","pmids":["26669263"],"confidence":"High","gaps":["In vivo coupling of H3.3 and H2A.Z deposition not fully mapped","Targeting specificity across the genome incomplete"]},{"year":2016,"claim":"Mapped a direct, damage-independent ATM-EP400 interaction via the EP400 N-terminus, identifying a constitutive signaling contact relevant to repair.","evidence":"Co-IP, heterologous reconstitution in Sf9 cells, dominant-negative fragment overexpression","pmids":["27814680"],"confidence":"Medium","gaps":["Functional consequence of the constitutive interaction unclear","Single lab"]},{"year":2017,"claim":"Demonstrated that Merkel cell polyomavirus small T recruits MYCL to the EP400 complex to activate genes and maintain carcinoma viability, defining a virus-host oncogenic mechanism.","evidence":"Large-scale IP-MS, ChIP-seq, RNA-seq, genome-wide CRISPR screen, transformation assays","pmids":["29028833"],"confidence":"High","gaps":["Which EP400-deposited variants drive target activation not resolved","Generalizability beyond MCC unclear"]},{"year":2019,"claim":"Established EP400 as a master regulator of myelinating glial differentiation, acting through Sox10/Myrf in oligodendrocytes and via H2A.Z redistribution that silences early regulators in Schwann cells.","evidence":"Conditional and temporally controlled knockout mice, ChIP/ChIP-seq, Ep400-Sox10 co-IP, Tfap2a double-knockout rescue","pmids":["31081019","31142747"],"confidence":"High","gaps":["How EP400 chooses which loci to clear H2A.Z from not defined","Maintenance vs differentiation roles delineated but molecular switch unknown"]},{"year":2021,"claim":"Resolved sub-complex heterogeneity by identifying JAZF1/MBTD1-containing and Phf5a-stabilized assemblies that couple TIP60 acetylation and variant deposition at specific loci and during class switch recombination.","evidence":"MS complex characterization, H2A.Z acetylation ChIP-seq after JAZF1 depletion; siRNA screen, ChIP, and DSB repair reporters at switch regions","pmids":["33445503","33938017"],"confidence":"Medium","gaps":["Functional division of labor among sub-complexes incomplete","Recruitment determinants of each sub-complex unclear"]},{"year":2023,"claim":"Positioned EP400 in a chromatin-accessibility pathway parallel to SWI/SNF at promoters, revealing synthetic lethality with therapeutic relevance, and tied the complex to neural crest metabolism and morphogenesis.","evidence":"Fast-acting SWI/SNF inhibitor with ATAC-seq and EP400-depletion epistasis; conditional KO with metabolic and proliferation analyses","pmids":["37922899","37024457"],"confidence":"High","gaps":["Why EP400 compensates at promoters but not enhancers unexplained","Metabolic phenotype mechanism in neural crest not resolved"]},{"year":2024,"claim":"Defined EP400's earliest developmental role: NFYA-directed H3.3 deposition at zygotic genome activation genes driving transcription elongation, with maternal loss causing 2-to-4-cell arrest.","evidence":"Oocyte-specific conditional KO, EP400-NFYA co-IP, H3.3 ChIP-seq, RNA-seq, embryo assays","pmids":["38493496"],"confidence":"High","gaps":["How NFYA targeting is coordinated with H2A.Z deposition unclear","Link to mitochondrial gene activation mechanistically thin"]},{"year":2025,"claim":"Revealed EP400 as a restrictor of HIV-1 transcription through paused-RNAPII control, with DMAP1 directly blocking Tat-TAR engagement, defining a Tat-dependent latency mechanism.","evidence":"shRNA screens, EP400/DMAP1/RNAPII ChIP-seq, DMAP1-Tat co-IP, Tat-deficient virus and RNAPII Ser2 phosphorylation assays, primary CD4+ T cells","pmids":["40842241","41414674"],"confidence":"High","gaps":["Whether ATPase/variant-deposition activity is required for latency unresolved","Generalization to cellular paused genes incomplete"]},{"year":2025,"claim":"Clarified the catalytic coupling within the complex, showing TIP60 pre-acetylates H2A.Z to promote its loading by EP400, and identified upstream PRMT5/SRSF1 control of complex integrity via KAT5 splicing.","evidence":"EP400 rapid-depletion ChIP-seq/ATAC-seq and biochemistry (preprint); Iso-Seq/RNA-seq with PRMT5 inhibition in MCC cells","pmids":["40846633"],"confidence":"Medium","gaps":["Acetylation-coupling model awaits peer review","Direct structural basis of H2A.Zac-H2B handoff not shown"]},{"year":null,"claim":"How EP400 achieves locus-specific targeting and reconciles its dual roles as a transcriptional activator and repressor across diverse cellular contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking sub-complex composition to activating vs repressive outcomes","Recruitment code beyond H3K4me3/Nanog/Sox10/NFYA incomplete","Structural basis of variant exchange and acetylation coupling unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,7,9,14]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14,30]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[14,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,14,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5,13]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[7,11,19]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9,14,22,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,14,24,27]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,10,15,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,19,23,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2,3,11]}],"complexes":["NuA4/TIP60 complex","p400/Domino complex"],"partners":["KAT5","TRRAP","DMAP1","NFYA","SOX10","MYC","RAD51","JAZF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96L91","full_name":"E1A-binding protein p400","aliases":["CAG repeat protein 32","Domino homolog","hDomino","Trinucleotide repeat-containing gene 12 protein","p400 kDa SWI2/SNF2-related protein"],"length_aa":3159,"mass_kda":343.5,"function":"Component of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. May be required for transcriptional activation of E2F1 and MYC target genes during cellular proliferation. The NuA4 complex ATPase and helicase activities seem to be, at least in part, contributed by the association of RUVBL1 and RUVBL2 with EP400. May regulate ZNF42 transcription activity. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96L91/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EP400","classification":"Common Essential","n_dependent_lines":1143,"n_total_lines":1208,"dependency_fraction":0.9461920529801324},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":10.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"ANKRD40","stoichiometry":0.2},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EP400","total_profiled":1310},"omim":[{"mim_id":"619700","title":"CILIATED LEFT-RIGHT ORGANIZER PROTEIN CONTAINING ZP-N DOMAINS; CIROZ","url":"https://www.omim.org/entry/619700"},{"mim_id":"608749","title":"BROMODOMAIN-CONTAINING PROTEIN 4; BRD4","url":"https://www.omim.org/entry/608749"},{"mim_id":"606265","title":"E1A-BINDING PROTEIN, 400-KD; EP400","url":"https://www.omim.org/entry/606265"},{"mim_id":"605077","title":"DNA METHYLTRANSFERASE 1-ASSOCIATED PROTEIN 1; DMAP1","url":"https://www.omim.org/entry/605077"},{"mim_id":"604788","title":"RUVB-LIKE AAA ATPase 2; RUVBL2","url":"https://www.omim.org/entry/604788"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EP400"},"hgnc":{"alias_symbol":["CAGH32","KIAA1498","P400","KIAA1818","DKFZP434I225"],"prev_symbol":["TNRC12"]},"alphafold":{"accession":"Q96L91","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96L91","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EP400","jax_strain_url":"https://www.jax.org/strain/search?query=EP400"},"sequence":{"accession":"Q96L91","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96L91.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96L91/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96L91"}},"corpus_meta":[{"pmid":"2554142","id":"PMC_2554142","title":"Primary structure and functional expression of the inositol 1,4,5-trisphosphate-binding protein P400.","date":"1989","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/2554142","citation_count":973,"is_preprint":false},{"pmid":"18614019","id":"PMC_18614019","title":"An RNAi screen of chromatin proteins identifies Tip60-p400 as a regulator of embryonic stem cell identity.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18614019","citation_count":359,"is_preprint":false},{"pmid":"2153079","id":"PMC_2153079","title":"A cerebellar Purkinje cell marker P400 protein is an inositol 1,4,5-trisphosphate (InsP3) receptor protein. 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signature","date":"2025-01-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.06.631535","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32347,"output_tokens":8090,"usd":0.109196,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17641,"output_tokens":6085,"usd":0.120165,"stage2_stop_reason":"end_turn"},"total_usd":0.229361,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"EP400 (p400) is a SWI2/SNF2-related 400 kDa ATPase that forms a large chromatin-remodeling complex with TRRAP/PAF400, DNA helicases TAP54alpha/beta, actin-like proteins, and the human Enhancer of Polycomb homolog. E1A binds this complex, and an E1A mutant defective in p400 binding is also defective in transformation, establishing p400 complex formation as essential for E1A-mediated transformation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry identification of complex components, E1A deletion mutant analysis, partial rescue with p400 fragments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mutant rescue experiments, multiple orthogonal methods in a focused mechanistic study\",\n      \"pmids\": [\"11509179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p400 is a component of the p53→p21 senescence pathway: acute shRNA depletion of p400 causes premature senescence in human fibroblasts (G1 arrest, p21 induction, SAHF, beta-gal staining), and these phenotypes are rescued by co-expression of p53-shRNA or p21-shRNA. p400 complex co-localizes with p53 on the p21 promoter, indicating p400 inhibits p53→p21 transcription.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation/ChIP showing p400 at p21 promoter, genetic epistasis via co-depletion of p53/p21\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis by double knockdown with defined phenotypic rescue, ChIP localization, multiple orthogonal methods\",\n      \"pmids\": [\"15655109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"p400 is required for E1A-induced apoptosis: E1A increases p400 expression and promotes co-association of p400-TRRAP with Rb; suppression of p400 by stable RNAi reduces ARF, p53 levels, and apoptosis in E1A-expressing cells. p400 is identified as a regulator of the ARF-p53 pathway.\",\n      \"method\": \"Stable RNAi knockdown, measurement of ARF/p53/apoptosis levels, co-immunoprecipitation of p400-TRRAP-Rb\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined apoptosis phenotype and pathway placement, single lab\",\n      \"pmids\": [\"15741165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tip60 and p400 (within the same complex) play antagonistic roles: p400 represses p21 expression in unstressed cells (allowing cell cycle progression), while Tip60 activates p53 target proapoptotic genes. p400 inhibits Tip60 function in the absence of DNA damage, and this inhibition is abolished after DNA damage. Both are required for UV-induced apoptosis.\",\n      \"method\": \"siRNA knockdown of p400 and Tip60 separately, measurement of p21 expression, cell cycle analysis, apoptosis assays, functional epistasis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with multiple phenotypic readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"16601686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VHL loss-induced senescence requires p400 (and Rb): acute VHL inactivation causes a senescent-like phenotype that is independent of p53 and HIF but dependent on Rb and the SWI2/SNF2 chromatin remodeler p400, placing p400 downstream of VHL in a tumor-suppressive senescence pathway.\",\n      \"method\": \"Genetic epistasis using shRNA against p400 and Rb in VHL-inactivated cells, in vitro and in vivo senescence assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by double knockdown, in vivo confirmation, single lab\",\n      \"pmids\": [\"18297059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In embryonic stem cells, p400 localization to promoters of both silent and active genes depends on H3K4me3, and Nanog depletion reduces p400 binding to target promoters without affecting H3K4me3 levels, indicating Tip60-p400 integrates Nanog and H3K4me3 signals to regulate ESC gene expression.\",\n      \"method\": \"RNAi screen, ChIP for p400 at promoters, Nanog knockdown epistasis, gene expression profiling\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-based localization, genetic epistasis with Nanog, multiple orthogonal methods, published in high-impact journal\",\n      \"pmids\": [\"18614019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"E1A targets p400 to stabilize and upregulate the oncoprotein Myc: E1A promotes coassociation of Myc and p400 at Myc target genes, leading to transcriptional induction. Forced Myc expression rescues activity of an E1A mutant defective in p400 binding, establishing Myc as the downstream target of the E1A-p400 interaction.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at Myc target genes, RNAi, rescue with Myc overexpression, E1A p400-binding mutant analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and genetic rescue, single lab\",\n      \"pmids\": [\"18413597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p400 ATPase activity and Tip60 acetyltransferase cooperate during DNA double-strand break (DSB) repair: p400 is recruited to DSBs by a mechanism independent of ATM but requiring Mdc1. p400 ATPase activity destabilizes nucleosomes in gamma-H2AX domains surrounding DSBs, which is required for RNF8-dependent chromatin ubiquitination and subsequent recruitment of BRCA1 and 53BP1.\",\n      \"method\": \"Chromatin fractionation, ATPase-dead mutant analysis, siRNA knockdown, recruitment assays for BRCA1/53BP1, ubiquitination assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ATPase-dead mutagenesis combined with multiple downstream readouts (nucleosome destabilization, ubiquitination, factor recruitment), multiple orthogonal methods\",\n      \"pmids\": [\"20876283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p400 is required for correct control of ROS metabolism: p400 depletion increases intracellular ROS levels and causes DNA damage. The effects of p400 on cell cycle progression, apoptosis, and senescence are dependent on ATM-dependent DDR pathways and involve direct transcriptional regulation of specific promoters including those controlling ROS metabolism.\",\n      \"method\": \"siRNA knockdown, ROS measurement, ATM siRNA epistasis, ChIP at specific promoters\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts with epistasis, ChIP validation, single lab\",\n      \"pmids\": [\"20548951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"p400/mDomino catalyzes ATP-dependent deposition of histone variant H2A.Z into nucleosomes to regulate gene expression, and is essential for adult bone marrow hematopoiesis and cell-cycle progression. Loss of p400/mDomino in MEFs causes S and G2/M phase defects, polyploidy, and multinucleation, with impaired expression of FoxM1 and c-Myc target cell-cycle genes.\",\n      \"method\": \"Conditional knockout mouse (Mx1-Cre), hematopoietic colony assay, cell-cycle FACS, DNA microarray, H2A.Z deposition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotypes, multiple orthogonal methods, in vivo and in vitro validation\",\n      \"pmids\": [\"20610385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p400 ATPase is required for DNA repair by homologous recombination (HR): p400-depleted cells are defective in HR-dependent repair, Rad51 recruitment to DSBs, and homology-directed repair. p400 and Rad51 are found in the same complex and both promote chromatin remodeling (decompaction) around DSBs.\",\n      \"method\": \"Co-immunoprecipitation of p400-Rad51 complex, siRNA knockdown, Rad51 focus formation assay, HR reporter assay, chromatin remodeling assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP showing complex formation, multiple functional assays (HR reporter, Rad51 foci, chromatin decompaction), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23266955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p400 deposits H2A.Z within the p21 promoter to repress p21 gene expression. During replicative senescence of IMR-90 fibroblasts, p400 levels decline and H2A.Z is lost from the p21 promoter, contributing to sustained p21 transcription and senescence onset.\",\n      \"method\": \"ChIP for H2A.Z and p400 at p21 promoter, nucleosome mapping, comparison between young and senescent cells\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — ChIP in multiple cell states with consistent findings, single lab, single method type\",\n      \"pmids\": [\"23146670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The p400/Brd8 complex promotes adipogenesis by incorporating histone variant H2A.Z at PPARgamma target gene promoters; shRNA-mediated knockdown of Brd8 or H2A.Z abolishes 3T3-L1 preadipocyte differentiation and blocks accumulation of PPARgamma, p400, and RNA Pol II at PPARgamma target genes.\",\n      \"method\": \"shRNA knockdown, lipid accumulation assay, ChIP for p400/PPARgamma/H2A.Z/Pol II at target gene promoters\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined adipogenesis phenotype, ChIP validation of mechanism, single lab\",\n      \"pmids\": [\"23064015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hdac6 co-purifies with Tip60-p400 complex from embryonic stem cells and is required for Tip60-p400 binding to many of its target genes. Unlike differentiated cells where Hdac6 is cytoplasmic, Hdac6 is largely nuclear in ESCs and interacts with Tip60-p400. Hdac6 does not appear to deacetylate histones in this context but is necessary for robust ESC differentiation.\",\n      \"method\": \"Co-purification/co-IP, ChIP for Hdac6 and Tip60-p400 at target promoters, siRNA knockdown, cellular fractionation, differentiation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-purification establishing complex membership, ChIP showing co-localization, epistatic knockdown, localization by fractionation, multiple orthogonal methods\",\n      \"pmids\": [\"24302573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EP400 deposits histone H3.3 into promoters and enhancers during gene activation alongside H2AZ. EP400 binds preferentially to acetylated H2AZ/H3.3-containing chromatin templates and is required for transcription stimulation by double-variant chromatin in vitro. EP400 efficiently exchanges H2A and H3.1 with H2AZ and H3.3, respectively, in a chromatin- and ATP-stimulated manner in vitro.\",\n      \"method\": \"Biochemical reconstitution of chromatin templates, in vitro transcription assay, histone exchange assay with recombinant histones, immobilized chromatin pulldown, ChIP-seq in vivo\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant histones and ATP dependence, in vitro transcription assay, in vivo ChIP-seq, multiple orthogonal methods\",\n      \"pmids\": [\"26669263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p400 ATPase acts as a brake on alternative end-joining (alt-EJ) DNA repair: p400 depletion increases alt-EJ frequency, generates large deletions after DSB repair, and this increase is dependent on CtIP-mediated resection. p400 depletion also leads to PARP and DNA ligase 3 recruitment to DSBs, conferring sensitivity to PARP inhibitors.\",\n      \"method\": \"Intracellular reporter substrates for alt-EJ, siRNA knockdown, CtIP epistasis, PARP inhibitor sensitivity assay, immunofluorescence for PARP/ligase 3 recruitment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter-based assay with epistasis, multiple functional readouts, single lab\",\n      \"pmids\": [\"26578561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATM kinase physically interacts with p400 ATPase independently of DNA damage state via the N-terminal domain of p400. This interaction can be reconstituted in Sf9 insect cells without mammalian bridging proteins, and overexpression of ATM-interacting p400 N-terminal fragments acts as a dominant negative, inhibiting DNA damage repair and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, heterologous reconstitution in Sf9 cells, dominant-negative overexpression, DNA repair and proliferation assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstituted interaction in Sf9 cells plus co-IP and dominant-negative functional validation, single lab\",\n      \"pmids\": [\"27814680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Merkel cell polyomavirus Small T antigen binds MYCL and recruits it to the 15-component EP400 histone acetyltransferase and chromatin remodeling complex. The ST-MYCL-EP400 complex binds together at specific gene promoters and activates their expression. MYCL and EP400 are required for maintenance of MCC cell viability and cooperate with ST to promote gene expression and cellular transformation.\",\n      \"method\": \"Large-scale immunoprecipitation with mass spectrometry, ChIP-seq, RNA-seq, CRISPR-Cas9 genome-wide screen, transformation assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mass spec identification of complex, ChIP-seq confirming co-occupancy, CRISPR screen confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"29028833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ep400 is required for oligodendrocyte terminal differentiation and myelination: Ep400-deficient oligodendrocyte precursors develop normally but fail to terminally differentiate. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene, and is required to induce Myrf, a central transcriptional regulator of myelination. Ep400 deletion in mature oligodendrocytes causes no phenotype, indicating Ep400 is dispensable for myelin maintenance.\",\n      \"method\": \"Conditional knockout mouse, ChIP for Ep400 at Myrf regulatory regions, co-immunoprecipitation of Ep400-Sox10, histological and myelin staining, immunofluorescence\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined myelination phenotype, co-IP, ChIP at target gene, multiple orthogonal methods, temporally controlled deletion\",\n      \"pmids\": [\"31081019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ep400 deletion in Schwann cells causes peripheral neuropathy through terminal differentiation defects. Mechanistically, Ep400 absence alters H2A.Z genomic distribution, causing H2A.Z to remain at promoters of early developmental regulators (Tfap2a, Pax3). Deletion of Tfap2a in Ep400-deficient Schwann cells provides partial rescue, indicating persistent expression of early regulators (maintained by Ep400 loss) mediates the defect.\",\n      \"method\": \"Conditional knockout mouse, ChIP-seq for H2A.Z distribution, genetic epistasis (double knockout with Tfap2a), histological analysis of peripheral nerves\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, genome-wide ChIP-seq, epistasis rescue via double KO, multiple orthogonal methods\",\n      \"pmids\": [\"31142747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JAZF1 is a member of a p400 sub-complex containing MBTD1 (but excluding ANP32E), identified by mass spectrometry-based H2A variant chaperone complex characterization. JAZF1 depletion leads to reduced H2A.Z acetylation at >1000 regulatory sites without affecting H2A.Z nucleosome positioning, suggesting JAZF1 recruits TIP60 acetyltransferase activity to regulate H2A.Z acetylation.\",\n      \"method\": \"Mass spectrometry identification of complex composition, ChIP-seq for H2A.Z acetylation after JAZF1 depletion, RNA-seq\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex identification, ChIP-seq functional validation, single lab\",\n      \"pmids\": [\"33445503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Phf5a stabilizes the p400 histone chaperone complex at immunoglobulin switch regions, which promotes deposition of H2A variants (H2AX and H2A.Z) critical for early DNA damage response and NHEJ, respectively, during class switch recombination. Depletion of Phf5a or p400 blocks repair of AID-induced and I-SceI-induced DNA DSBs.\",\n      \"method\": \"siRNA screen, ChIP for p400 at switch regions, H2A variant deposition assays, I-SceI reporter for DSB repair, flow cytometric CSR assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA-based functional screen, ChIP, DSB repair reporter, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33938017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EP400/TIP60 remodeler compensates for loss of SWI/SNF activity by reestablishing chromatin accessibility at most gene promoters (but not enhancers) during prolonged SWI/SNF inhibition. EP400 and SWI/SNF show synthetic lethality in cancer cell lines. This places EP400 in a parallel chromatin accessibility pathway to SWI/SNF at promoters.\",\n      \"method\": \"Fast-acting SWI/SNF inhibitor treatment, ATAC-seq for chromatin accessibility, genetic epistasis with EP400 depletion, synthetic lethality in cancer cell lines\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chemical-genetic approach with fast-acting inhibitor, genome-wide ATAC-seq, synthetic lethality validation across cancer lines, multiple orthogonal methods\",\n      \"pmids\": [\"37922899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Inactivation of Ep400 (or Kat5/Tip60) in cranial neural crest cells severely impairs carbohydrate and amino acid metabolism, decreases protein synthesis, proliferation, and survival of neural crest cells, leading to loss of most facial structures. Heterozygous Kat5 loss impairs palatogenesis, implicating the Tip60/Ep400 complex in facial morphogenesis.\",\n      \"method\": \"CRISPR/Cas9 genome editing and conditional mutagenesis in mouse, metabolic analysis, histology, immunofluorescence for proliferation/survival markers\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, metabolic and proliferation readouts, single lab\",\n      \"pmids\": [\"37024457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EP400 deposits H3.3 into promoters of major zygotic genome activation (ZGA) genes in mouse oocytes and early embryos. EP400 forms a protein complex with NFYA at ZGA gene promoters, modulates H3.3 distribution between euchromatin and heterochromatin, promotes transcription elongation, and activates genes regulating mitochondrial functions and TCA cycle enzymes. Maternal Ep400 depletion causes developmental arrest at the 2-to-4-cell stage.\",\n      \"method\": \"Oocyte-specific conditional knockout, co-immunoprecipitation of EP400-NFYA, ChIP-seq for H3.3 distribution, RNA-seq, embryo developmental assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, co-IP of complex, ChIP-seq, RNA-seq, defined developmental phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"38493496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Adenovirus small e1a promotes derepression of Alu retrotransposons via physical interaction with EP400 chromatin remodeler at YAP/TEAD- and AP-1-bound enhancers; EP400 ablation abrogates e1a-induced Alu derepression. This establishes EP400 as required for e1a-mediated epigenomic changes at enhancer Alus.\",\n      \"method\": \"EP400 ChIP-seq, ATAC-seq/epigenome profiling, EP400 ablation by CRISPR, RNA-seq for Alu transcription, co-immunoprecipitation of e1a-EP400\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, co-IP, CRISPR ablation with functional readout, single lab\",\n      \"pmids\": [\"39011896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EP400 suppresses melanoma cell growth via interaction with c-MYC: a LINC00944-encoded peptide disrupts the EP400-MYC interaction, reduces c-MYC protein expression, and represses MYC transcriptional activity including fatty acid and glucose metabolism target genes.\",\n      \"method\": \"Co-immunoprecipitation of EP400-MYC complex, peptide competition assay, MYC reporter/expression assays, cell proliferation assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP of EP400-MYC and competition assay, single lab, single method for complex disruption\",\n      \"pmids\": [\"39586403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The p400 complex promotes HIV-1 latency by suppressing viral transcription: EP400 and its complex partner DMAP1 co-localize with paused RNA Polymerase II at transcriptional start sites, and their depletion markedly increases RNAPII pause release at the HIV-1 locus. EP400 depletion also increases expression of T-cell factors that activate HIV-1 transcription.\",\n      \"method\": \"shRNAmir pooled screen, ChIP-seq for EP400/DMAP1/RNAPII at HIV locus and cellular genes, HIV transcription reporter assays, primary CD4+ T cell assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, functional screen, primary cell validation, single lab\",\n      \"pmids\": [\"40842241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EP400 ATPase (with DMAP1) restricts HIV-1 transcription in a Tat-dependent manner: EP400 associates with RNAPII C-terminal domain, while DMAP1 directly binds the viral transactivator Tat's basic domain, blocking Tat-TAR RNA interaction and limiting p-TEFb-mediated RNAPII Ser2 phosphorylation and elongation. Repression requires simultaneous interactions among EP400, DMAP1, and Tat.\",\n      \"method\": \"Co-immunoprecipitation of DMAP1-Tat, EP400-RNAPII interaction assays, ChIP-seq, Tat-deficient virus experiments, RNAPII Ser2 phosphorylation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein interaction mapped (DMAP1-Tat, EP400-RNAPII CTD), mechanistic epistasis with Tat-deficient virus, ChIP-seq, RNAPII modification readout, multiple orthogonal methods\",\n      \"pmids\": [\"41414674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT5 sustains the Tip60-EP400 complex in Merkel cell carcinoma via SRSF1: PRMT5-mediated modification of SRSF1 enhances its recruitment to m6A-modified RNA, ensuring proper KAT5 (Tip60) splicing and Tip60-EP400 activity. PRMT5 inhibition disrupts SRSF1 recruitment, leading to splicing defects (exon skipping, intron retention) in KAT5 transcripts and impaired Tip60-EP400 complex activity.\",\n      \"method\": \"RNA-seq, Iso-Seq for alternative splicing analysis, PRMT5 inhibition, SRSF1 modification assays, complex activity assays in MCC cells\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Iso-Seq for splicing, RNA-seq, mechanistic connection between PRMT5/SRSF1/KAT5 splicing and EP400 complex integrity, single lab\",\n      \"pmids\": [\"40846633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EP400 (within NuA4/TIP60) pre-acetylates H2A.Z to facilitate H2A.Zac-H2B dimer association with the complex before EP400-mediated incorporation into chromatin at gene promoters, positively regulating transcription. This establishes a coordinated mechanism where TIP60 acetyltransferase activity and EP400 remodeling activity are functionally coupled.\",\n      \"method\": \"EP400 rapid depletion system, functional genomics (ChIP-seq, ATAC-seq), biochemical analyses of H2A.Z acetylation and chromatin incorporation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EP400 rapid depletion with genomic and biochemical readouts, multiple orthogonal methods; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"EP400 is the catalytic ATPase subunit of the NuA4/TIP60 chromatin remodeling complex that drives ATP-dependent exchange of canonical histones for variants H2A.Z and H3.3 at gene promoters and enhancers; it cooperates with TIP60 acetyltransferase activity (which pre-acetylates H2A.Z before loading), recruits transcription factors (e.g., Nanog, Sox10, NFYA), regulates RNAPII pausing and elongation, promotes DNA repair by homologous recombination and NHEJ through nucleosome destabilization at DSBs, suppresses p53→p21 transcription to prevent premature senescence, and is essential for embryonic hematopoiesis, oligodendrocyte myelination, Schwann cell differentiation, ESC identity, and early embryonic zygotic genome activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EP400 (p400) is the SWI2/SNF2-related ATPase subunit of a large NuA4/TIP60 chromatin-remodeling complex that catalyzes ATP-dependent exchange of canonical histones for the variants H2A.Z and H3.3 at gene promoters and enhancers to control transcription [#0, #14]. EP400 efficiently swaps H2A and H3.1 for H2A.Z and H3.3 in a chromatin- and ATP-stimulated reaction, binds preferentially to acetylated H2A.Z/H3.3 templates, and its remodeling activity is functionally coupled to the TIP60 acetyltransferase, which pre-acetylates H2A.Z before incorporation [#14, #30]. Deposition of these variants directs context-specific gene programs: EP400 integrates Nanog and H3K4me3 signals at promoters to maintain embryonic stem cell identity [#5, #13], partners with Sox10 to induce Myrf during oligodendrocyte differentiation [#18], controls H2A.Z distribution to silence early regulators (Tfap2a, Pax3) during Schwann cell maturation [#19], cooperates with PPARgamma during adipogenesis [#12], and forms a complex with NFYA to drive H3.3 deposition and transcription elongation at zygotic genome activation genes, with maternal depletion arresting embryos at the 2-to-4-cell stage [#24]. Through H2A.Z deposition at the p21 promoter, EP400 represses the p53\\u2192p21 axis to permit cell-cycle progression and prevent premature senescence; its loss triggers p53/p21-dependent senescence and is required for the senescence response downstream of VHL [#1, #11, #4]. EP400 ATPase activity also destabilizes nucleosomes around DNA double-strand breaks, a step required for RNF8-dependent ubiquitination and recruitment of BRCA1, 53BP1, and Rad51, thereby promoting homologous recombination and NHEJ while restraining mutagenic alternative end-joining [#7, #10, #15]. EP400 functions in parallel to SWI/SNF in establishing promoter chromatin accessibility, producing synthetic lethality in cancer cells [#22], and is exploited by viral oncoproteins\\u2014adenovirus E1A targets EP400 to upregulate Myc and drive transformation, and Merkel cell polyomavirus small T recruits MYCL to the EP400 complex to maintain carcinoma viability [#0, #6, #17].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established EP400 as the ATPase core of a defined multi-subunit chromatin remodeling complex and linked that complex to viral oncogenic transformation, framing the biochemical identity of the protein.\",\n      \"evidence\": \"Co-IP and mass spectrometry of the complex plus E1A deletion-mutant transformation assays\",\n      \"pmids\": [\"11509179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic substrate of the ATPase not yet defined\", \"Histone variant exchange activity not yet demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed EP400 as a repressor of the p53\\u2192p21 senescence pathway, explaining why loss of this remodeler drives premature senescence.\",\n      \"evidence\": \"shRNA depletion in human fibroblasts with p53/p21 co-depletion rescue and ChIP at the p21 promoter\",\n      \"pmids\": [\"15655109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of repression at p21 not yet defined (variant deposition shown later)\", \"Whether repression is direct ATPase-dependent unresolved here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed EP400 and TIP60 within the same complex have antagonistic, DNA-damage-gated outputs, establishing a switch between proliferative repression and proapoptotic activation.\",\n      \"evidence\": \"Separate siRNA knockdown of p400 and Tip60 with p21, cell-cycle, and apoptosis readouts\",\n      \"pmids\": [\"16601686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of p400 inhibition of Tip60 not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected EP400 to ESC identity by showing its promoter recruitment depends on H3K4me3 and Nanog, defining how the complex is targeted in pluripotent cells.\",\n      \"evidence\": \"RNAi screen, p400 ChIP at promoters, Nanog knockdown epistasis in ESCs\",\n      \"pmids\": [\"18614019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct reader of H3K4me3 within the complex not identified\", \"Functional consequence at individual target genes limited\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended EP400's senescence role downstream of a distinct tumor-suppressor input (VHL) and to oncoprotein-driven apoptosis and Myc activation, broadening its tumor-suppressive and oncogenic context.\",\n      \"evidence\": \"shRNA epistasis in VHL-inactivated cells; stable RNAi with apoptosis/ARF readouts; co-IP and ChIP at Myc targets\",\n      \"pmids\": [\"18297059\", \"15741165\", \"18413597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How one remodeler produces both pro- and anti-proliferative outputs not mechanistically unified\", \"Single-lab contexts\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined EP400's role in DNA double-strand break repair, showing its ATPase destabilizes nucleosomes in gamma-H2AX domains to license downstream ubiquitination and repair-factor recruitment.\",\n      \"evidence\": \"ATPase-dead mutant analysis, chromatin fractionation, BRCA1/53BP1 recruitment and ubiquitination assays\",\n      \"pmids\": [\"20876283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Mdc1-dependent recruitment not fully mapped\", \"Histone variant identity at DSBs not resolved here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified EP400 as the catalyst of H2A.Z deposition and tied this activity to hematopoiesis, cell-cycle gene control, and ROS metabolism in vivo.\",\n      \"evidence\": \"Conditional knockout mouse, H2A.Z deposition assays, cell-cycle FACS, microarray; ROS and ATM-epistasis assays\",\n      \"pmids\": [\"20610385\", \"20548951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro variant-exchange biochemistry not yet shown\", \"Relationship of ROS phenotype to variant deposition unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined EP400 as a homologous recombination factor and a brake on mutagenic alternative end-joining, refining its role to specific DSB repair pathway choice.\",\n      \"evidence\": \"p400-Rad51 co-IP, HR and alt-EJ reporter assays, CtIP epistasis, PARP inhibitor sensitivity, chromatin decompaction assays\",\n      \"pmids\": [\"23266955\", \"26578561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How EP400 biases pathway choice mechanistically not fully resolved\", \"alt-EJ findings single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mechanistically linked EP400-driven H2A.Z deposition at the p21 promoter to senescence onset and to lineage-specific gene activation in adipogenesis, generalizing variant deposition as the effector mechanism.\",\n      \"evidence\": \"ChIP for H2A.Z/p400 at p21 in young vs senescent cells; Brd8/H2A.Z knockdown and ChIP at PPARgamma targets in 3T3-L1\",\n      \"pmids\": [\"23146670\", \"23064015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between H2A.Z loss and senescence vs correlation not fully disentangled\", \"Single-method ChIP studies\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed Hdac6 as an unexpected nuclear partner required for Tip60-p400 target binding in ESCs, expanding the complex's composition in pluripotent cells.\",\n      \"evidence\": \"Co-purification, ChIP co-localization, fractionation, and differentiation assays in ESCs\",\n      \"pmids\": [\"24302573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic role of Hdac6 in this context excluded but its mechanistic contribution unclear\", \"How Hdac6 promotes complex recruitment unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the definitive biochemical demonstration that EP400 exchanges both H2A.Z and H3.3 into chromatin in an ATP-stimulated manner and that double-variant chromatin stimulates transcription.\",\n      \"evidence\": \"In vitro reconstitution with recombinant histones, in vitro transcription, immobilized chromatin pulldown, and ChIP-seq\",\n      \"pmids\": [\"26669263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo coupling of H3.3 and H2A.Z deposition not fully mapped\", \"Targeting specificity across the genome incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped a direct, damage-independent ATM-EP400 interaction via the EP400 N-terminus, identifying a constitutive signaling contact relevant to repair.\",\n      \"evidence\": \"Co-IP, heterologous reconstitution in Sf9 cells, dominant-negative fragment overexpression\",\n      \"pmids\": [\"27814680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the constitutive interaction unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that Merkel cell polyomavirus small T recruits MYCL to the EP400 complex to activate genes and maintain carcinoma viability, defining a virus-host oncogenic mechanism.\",\n      \"evidence\": \"Large-scale IP-MS, ChIP-seq, RNA-seq, genome-wide CRISPR screen, transformation assays\",\n      \"pmids\": [\"29028833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which EP400-deposited variants drive target activation not resolved\", \"Generalizability beyond MCC unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established EP400 as a master regulator of myelinating glial differentiation, acting through Sox10/Myrf in oligodendrocytes and via H2A.Z redistribution that silences early regulators in Schwann cells.\",\n      \"evidence\": \"Conditional and temporally controlled knockout mice, ChIP/ChIP-seq, Ep400-Sox10 co-IP, Tfap2a double-knockout rescue\",\n      \"pmids\": [\"31081019\", \"31142747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EP400 chooses which loci to clear H2A.Z from not defined\", \"Maintenance vs differentiation roles delineated but molecular switch unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved sub-complex heterogeneity by identifying JAZF1/MBTD1-containing and Phf5a-stabilized assemblies that couple TIP60 acetylation and variant deposition at specific loci and during class switch recombination.\",\n      \"evidence\": \"MS complex characterization, H2A.Z acetylation ChIP-seq after JAZF1 depletion; siRNA screen, ChIP, and DSB repair reporters at switch regions\",\n      \"pmids\": [\"33445503\", \"33938017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional division of labor among sub-complexes incomplete\", \"Recruitment determinants of each sub-complex unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned EP400 in a chromatin-accessibility pathway parallel to SWI/SNF at promoters, revealing synthetic lethality with therapeutic relevance, and tied the complex to neural crest metabolism and morphogenesis.\",\n      \"evidence\": \"Fast-acting SWI/SNF inhibitor with ATAC-seq and EP400-depletion epistasis; conditional KO with metabolic and proliferation analyses\",\n      \"pmids\": [\"37922899\", \"37024457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why EP400 compensates at promoters but not enhancers unexplained\", \"Metabolic phenotype mechanism in neural crest not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined EP400's earliest developmental role: NFYA-directed H3.3 deposition at zygotic genome activation genes driving transcription elongation, with maternal loss causing 2-to-4-cell arrest.\",\n      \"evidence\": \"Oocyte-specific conditional KO, EP400-NFYA co-IP, H3.3 ChIP-seq, RNA-seq, embryo assays\",\n      \"pmids\": [\"38493496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NFYA targeting is coordinated with H2A.Z deposition unclear\", \"Link to mitochondrial gene activation mechanistically thin\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed EP400 as a restrictor of HIV-1 transcription through paused-RNAPII control, with DMAP1 directly blocking Tat-TAR engagement, defining a Tat-dependent latency mechanism.\",\n      \"evidence\": \"shRNA screens, EP400/DMAP1/RNAPII ChIP-seq, DMAP1-Tat co-IP, Tat-deficient virus and RNAPII Ser2 phosphorylation assays, primary CD4+ T cells\",\n      \"pmids\": [\"40842241\", \"41414674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATPase/variant-deposition activity is required for latency unresolved\", \"Generalization to cellular paused genes incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Clarified the catalytic coupling within the complex, showing TIP60 pre-acetylates H2A.Z to promote its loading by EP400, and identified upstream PRMT5/SRSF1 control of complex integrity via KAT5 splicing.\",\n      \"evidence\": \"EP400 rapid-depletion ChIP-seq/ATAC-seq and biochemistry (preprint); Iso-Seq/RNA-seq with PRMT5 inhibition in MCC cells\",\n      \"pmids\": [\"40846633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetylation-coupling model awaits peer review\", \"Direct structural basis of H2A.Zac-H2B handoff not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EP400 achieves locus-specific targeting and reconciles its dual roles as a transcriptional activator and repressor across diverse cellular contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking sub-complex composition to activating vs repressive outcomes\", \"Recruitment code beyond H3K4me3/Nanog/Sox10/NFYA incomplete\", \"Structural basis of variant exchange and acetylation coupling unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 7, 9, 14]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14, 30]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [14, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 14, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5, 13]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [7, 11, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9, 14, 22, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 14, 24, 27]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 10, 15, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 19, 23, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 3, 11]}\n    ],\n    \"complexes\": [\"NuA4/TIP60 complex\", \"p400/Domino complex\"],\n    \"partners\": [\"KAT5\", \"TRRAP\", \"DMAP1\", \"NFYA\", \"Sox10\", \"MYC\", \"Rad51\", \"JAZF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}