{"gene":"EPC1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2004,"finding":"EPC1 was identified as a binding partner of transcriptional repressor E2F6 via yeast two-hybrid screen; E2F6, DP1, and EPC1 form a stable core complex with repressive activity both in vitro and in vivo; EPC1 also interacts with the proliferation-specific polycomb protein EZH2, and affinity purification showed E2F6, DP1, EPC1, EZH2, and Sin3B co-elute as a novel complex that exists only in proliferating cells.","method":"Yeast two-hybrid screen, in vitro binding assay, affinity purification/co-elution, cell-based repression assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal yeast two-hybrid plus in vitro and in vivo complex formation, multiple orthogonal methods in single study","pmids":["15536069"],"is_preprint":false},{"year":2015,"finding":"EPC1 physically interacts with E2F1 (E2F1 binds the EPC1 promoter; EPC1 co-localizes with E2F1 in the nucleus); depletion of EPC1 potentiates E2F1-mediated apoptosis after genotoxic treatment and abolishes tumor cell motility; EPC1 modulates E2F1 transcriptional activity in a target-gene-specific manner, activating anti-apoptotic genes (BCL-2, Survivin/BIRC5) and silencing pro-apoptotic targets.","method":"ChIP, co-immunoprecipitation, nuclear co-localization, siRNA knockdown with apoptosis and motility readouts, reporter/gene expression assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, co-IP, KD phenotypes) in single lab","pmids":["26350215"],"is_preprint":false},{"year":2013,"finding":"EPC1 and EPC2, as components of the EP400 complex, are required for the clonogenic and leukemia stem cell potential of MLL-mutated AML cells; EPC1/EPC2 knockdown induces apoptosis in murine MLL-AF9 AML cells and causes MYC protein accumulation; pharmacological inhibition of MYC:MAX dimerization or concomitant MYC knockdown reduces apoptosis following EPC1 KD, placing EPC1 upstream of MYC protein levels.","method":"Targeted shRNA knockdown screen, colony-forming assays, transplantation leukemia stem cell assay, transcriptional profiling, pharmacological MYC inhibition, epistasis by concomitant KD","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus functional phenotypic readouts, single lab, multiple orthogonal methods","pmids":["24166297"],"is_preprint":false},{"year":2012,"finding":"In yeast Piccolo NuA4 complex, the EPcA homology domain of Epl1 (ortholog of human EPC1) contains a short basic region at its N-terminus that is necessary for nucleosomal histone H4/H2A acetyltransferase activity; this basic region is positioned in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and nucleosomal DNA when Piccolo NuA4 is bound to the nucleosome, but is not required for nucleosome binding per se.","method":"In vitro nucleosomal histone acetyltransferase assay, site-directed mutagenesis, site-specific cross-linking proximity assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstituted HAT assay with mutagenesis and structural proximity mapping, multiple orthogonal methods","pmids":["23109429"],"is_preprint":false},{"year":2017,"finding":"In S. cerevisiae, deletion of Epl1 (Enhancer of polycomb, ortholog of human EPC1) can be bypassed by loss of the Rpd3L deacetylase complex, a suppression property shared with the catalytic subunit Esa1; dissection of Epl1 domains shows distinct regions are required in vivo for interaction with specific NuA4 subunits, histone acetylation, and chromatin targeting, demonstrating that Epl1 promotes Esa1 catalytic activity through structural scaffolding.","method":"Genetic suppressor bypass screen, deletion mapping, in vivo histone acetylation assays, chromatin targeting assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus domain dissection and functional assays, single lab","pmids":["28108589"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the MBTD1–EPC1 complex revealed that a hydrophobic C-terminal fragment of EPC1 engages the MBT repeats of MBTD1 at a site distinct from the H4K20me-binding pocket; cellular assays validated key interface residues, establishing that EPC1 recruits MBTD1 into the NuA4/TIP60 complex to influence transcription and DNA repair pathway choice.","method":"X-ray crystallography, site-directed mutagenesis, cellular interaction assays (co-IP, functional readouts for DNA repair)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validated by multiple cellular assays in single rigorous study","pmids":["32209463"],"is_preprint":false},{"year":2024,"finding":"EPC1 and EPC2 regulate hematopoietic stem and progenitor cell (HSPC) proliferation; depletion of EPC1/2 reduces HSPC numbers in the aorta-gonad mesonephros and caudal hematopoietic tissue by impairing proliferation; mechanistically, EPC1/2 regulate histone H3 acetylation and control expression of DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation, cooperating with transcription factors SRF and FOXR2.","method":"Morpholino/genetic knockdown in zebrafish, K562 cell knockdown, ChIP-based H3 acetylation assays, gene expression analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype plus chromatin (H3 acetylation) mechanistic readout, single lab","pmids":["38439957"],"is_preprint":false},{"year":2026,"finding":"CCER1 nuclear condensates recruit TIP60 and EPC1 subunits to the NuA4 acetyltransferase complex in spermatids; disruption of CCER1 droplets impairs TIP60–EPC1 interaction and reduces histone H4 hyperacetylation in nucleosomes, leading to defective DNA strand breakage and insufficient histone-to-protamine replacement during spermiogenesis.","method":"Immunoprecipitation-mass spectrometry (CCER1-Tag knock-in mice), co-IP validation, H4 acetylation assay, genetic knock-in/knockout in mice","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus co-IP validation and functional phenotypic readout in knock-in mouse model, single lab","pmids":["41670399"],"is_preprint":false}],"current_model":"EPC1 (Enhancer of Polycomb 1) is a non-catalytic scaffolding subunit of the NuA4/TIP60 histone acetyltransferase complex that uses its EPcA domain basic region to orient Esa1/TIP60 for nucleosomal H4/H2A acetylation, recruits MBTD1 into the complex via a hydrophobic C-terminal interface to regulate DNA repair pathway choice, forms a repressive complex with E2F6–DP1 and the proliferation-specific EZH2, modulates E2F1 transcriptional activity to promote anti-apoptotic gene expression and suppress DNA-damage-induced apoptosis, sustains MLL-leukemia stem cell potential partly by preventing aberrant MYC accumulation, and supports hematopoietic stem/progenitor cell proliferation through regulation of H3 acetylation and DLST expression."},"narrative":{"mechanistic_narrative":"EPC1 (Enhancer of Polycomb 1) is a non-catalytic scaffolding subunit of the NuA4/TIP60 histone acetyltransferase complex that orients catalytic activity toward nucleosomal histones and couples it to specific chromatin outcomes [PMID:23109429, PMID:28108589]. In the yeast Piccolo NuA4 ortholog Epl1, a short basic region within the conserved EPcA domain is positioned near the H2A tail, the H4 globular region, and nucleosomal DNA, and is required for nucleosomal H4/H2A acetyltransferase activity without being needed for nucleosome binding, while distinct Epl1 domains mediate subunit interaction, histone acetylation, and chromatin targeting — establishing that EPC1 promotes Esa1/TIP60 catalysis through structural scaffolding [PMID:23109429, PMID:28108589]. A hydrophobic C-terminal fragment of EPC1 engages the MBT repeats of MBTD1 at a site distinct from the H4K20me-binding pocket, recruiting MBTD1 into the complex to influence transcription and DNA-repair pathway choice [PMID:32209463]. Beyond its complex-assembly role, EPC1 acts in transcriptional control: it forms a proliferation-specific repressive complex with E2F6, DP1, EZH2, and Sin3B [PMID:15536069], and modulates E2F1 activity in a target-specific manner, activating anti-apoptotic genes (BCL-2, BIRC5) while suppressing genotoxin-induced apoptosis and supporting tumor cell motility [PMID:26350215]. In hematopoiesis, EPC1 (with EPC2) is required for MLL-rearranged leukemia stem cell potential, acting upstream of MYC protein levels to prevent aberrant MYC accumulation [PMID:24166297], and sustains normal hematopoietic stem/progenitor proliferation by regulating H3 acetylation and DLST expression in cooperation with SRF and FOXR2 [PMID:38439957]. EPC1 is also recruited with TIP60 by CCER1 nuclear condensates during spermiogenesis to drive H4 hyperacetylation needed for histone-to-protamine exchange [PMID:41670399].","teleology":[{"year":2004,"claim":"Established EPC1 as a partner of transcriptional repressors, placing it in a proliferation-specific repressive complex rather than acting only as a generic acetyltransferase subunit.","evidence":"Yeast two-hybrid, in vitro binding, affinity purification/co-elution and cell-based repression assays defining an E2F6–DP1–EPC1–EZH2–Sin3B complex","pmids":["15536069"],"confidence":"High","gaps":["Does not define which EPC1 region mediates these interactions","Repressed target genes not directly enumerated","Relationship to the NuA4/TIP60 complex not addressed"]},{"year":2012,"claim":"Defined the structural basis for how the EPcA domain promotes catalysis, showing the basic region orients the complex on the nucleosome for H4/H2A acetylation independent of nucleosome binding.","evidence":"In vitro reconstituted nucleosomal HAT assays with site-directed mutagenesis and site-specific cross-linking proximity mapping in yeast Piccolo NuA4 (Epl1 ortholog)","pmids":["23109429"],"confidence":"High","gaps":["Demonstrated in yeast Epl1, not human EPC1 directly","Does not address full NuA4/TIP60 complex behavior","Atomic-resolution structure not obtained"]},{"year":2013,"claim":"Connected EPC1 to disease-relevant biology by placing it upstream of MYC protein levels in MLL-leukemia stem cells.","evidence":"shRNA knockdown screen, colony-forming and transplantation leukemia stem cell assays, transcriptional profiling, and pharmacological/genetic MYC epistasis in murine MLL-AF9 AML","pmids":["24166297"],"confidence":"Medium","gaps":["Mechanism by which EPC1 limits MYC accumulation unresolved","Chromatin/acetylation events at MYC not mapped","Single-lab finding without orthogonal validation"]},{"year":2015,"claim":"Showed EPC1 modulates E2F1 transcriptional output to bias cells toward survival, linking it to apoptosis suppression and tumor cell motility.","evidence":"ChIP, co-IP, nuclear co-localization, siRNA knockdown with apoptosis/motility readouts and reporter assays","pmids":["26350215"],"confidence":"Medium","gaps":["Whether NuA4/TIP60 acetyltransferase activity mediates target selectivity not shown","Direct vs indirect regulation of pro/anti-apoptotic targets not fully resolved","Single-lab study"]},{"year":2017,"claim":"Demonstrated genetically that EPC1/Epl1 is functionally interchangeable with the catalytic subunit in promoting acetylation, formalizing its scaffolding role through domain dissection.","evidence":"Genetic suppressor bypass screen (Rpd3L loss), deletion mapping, and in vivo histone acetylation and chromatin targeting assays in S. cerevisiae","pmids":["28108589"],"confidence":"Medium","gaps":["Performed in yeast; human EPC1 domain assignments inferred","Specific subunit-binding interfaces not structurally resolved here","Single-lab study"]},{"year":2020,"claim":"Resolved how EPC1 recruits MBTD1 into NuA4/TIP60, providing a molecular handle linking complex composition to DNA-repair pathway choice.","evidence":"X-ray crystallography of the MBTD1–EPC1 complex with interface mutagenesis validated in cellular co-IP and DNA-repair readouts","pmids":["32209463"],"confidence":"High","gaps":["Quantitative impact of MBTD1 recruitment on specific repair pathways not fully defined","Interplay with the E2F1/E2F6 functions of EPC1 unaddressed"]},{"year":2024,"claim":"Extended EPC1 function to normal hematopoietic stem/progenitor proliferation, identifying DLST as an H3-acetylation-regulated target.","evidence":"Morpholino/genetic knockdown in zebrafish, K562 knockdown, ChIP-based H3 acetylation and gene expression analysis with SRF/FOXR2 cooperation","pmids":["38439957"],"confidence":"Medium","gaps":["Direct EPC1 occupancy at the DLST locus not shown","Mechanism of cooperation with SRF/FOXR2 unresolved","Single-lab study"]},{"year":2026,"claim":"Showed EPC1 is recruited by phase-separated CCER1 condensates with TIP60 to drive H4 hyperacetylation required for chromatin remodeling in spermiogenesis.","evidence":"IP-MS in CCER1-Tag knock-in mice, co-IP, H4 acetylation assays, and knock-in/knockout mouse phenotyping","pmids":["41670399"],"confidence":"Medium","gaps":["Direct CCER1–EPC1 contact vs indirect recruitment not distinguished","Genomic targets of CCER1-directed acetylation not mapped","Single-lab study"]},{"year":null,"claim":"How EPC1's distinct activities — NuA4/TIP60 scaffolding, MBTD1 recruitment, E2F-family transcriptional regulation, and MYC restraint — are integrated within a single protein and coordinated across cell contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length human EPC1 within NuA4/TIP60","Whether E2F6/E2F1 regulation requires acetyltransferase activity unknown","Molecular link between EPC1 and MYC protein turnover undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]}],"complexes":["NuA4/TIP60 histone acetyltransferase complex","Piccolo NuA4","EP400 complex","E2F6–DP1–EPC1–EZH2–Sin3B repressive complex"],"partners":["E2F6","TFDP1","EZH2","SIN3B","E2F1","MBTD1","EPC2","CCER1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H2F5","full_name":"Enhancer of polycomb homolog 1","aliases":[],"length_aa":836,"mass_kda":93.5,"function":"Component of the NuA4 histone acetyltransferase (HAT) complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:14966270). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR) (PubMed:27153538). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone acetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). In the NuA4 complex, EPC1 is required to recruit MBTD1 into the complex (PubMed:32209463)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H2F5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPC1","classification":"Not Classified","n_dependent_lines":328,"n_total_lines":1208,"dependency_fraction":0.271523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPC1","total_profiled":1310},"omim":[{"mim_id":"611549","title":"SODIUM LEAK CHANNEL, NONSELECTIVE; NALCN","url":"https://www.omim.org/entry/611549"},{"mim_id":"610999","title":"ENHANCER OF POLYCOMB HOMOLOG 1; EPC1","url":"https://www.omim.org/entry/610999"},{"mim_id":"609539","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 2; ARID2","url":"https://www.omim.org/entry/609539"},{"mim_id":"607585","title":"ATM SERINE/THREONINE KINASE; ATM","url":"https://www.omim.org/entry/607585"},{"mim_id":"607493","title":"INHIBITOR OF GROWTH 3; ING3","url":"https://www.omim.org/entry/607493"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":141.2}],"url":"https://www.proteinatlas.org/search/EPC1"},"hgnc":{"alias_symbol":["Epl1"],"prev_symbol":[]},"alphafold":{"accession":"Q9H2F5","domains":[{"cath_id":"-","chopping":"105-183","consensus_level":"high","plddt":87.9995,"start":105,"end":183},{"cath_id":"-","chopping":"435-485","consensus_level":"medium","plddt":74.8531,"start":435,"end":485},{"cath_id":"1.20.5","chopping":"229-278","consensus_level":"high","plddt":96.0542,"start":229,"end":278}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2F5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2F5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H2F5-F1-predicted_aligned_error_v6.png","plddt_mean":56.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPC1","jax_strain_url":"https://www.jax.org/strain/search?query=EPC1"},"sequence":{"accession":"Q9H2F5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H2F5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H2F5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H2F5"}},"corpus_meta":[{"pmid":"16397222","id":"PMC_16397222","title":"Consistent 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hygiene","url":"https://pubmed.ncbi.nlm.nih.gov/27091868","citation_count":12,"is_preprint":false},{"pmid":"29559147","id":"PMC_29559147","title":"Evaluation of Echinococcus granulosus recombinant EgAgB8/1, EgAgB8/2 and EPC1 antigens in the diagnosis of cystic echinococcosis in buffaloes.","date":"2018","source":"Veterinary parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/29559147","citation_count":10,"is_preprint":false},{"pmid":"32426296","id":"PMC_32426296","title":"Preliminary Evaluation of Recombinant EPC1 and TPx for Serological Diagnosis of Animal Cystic Echinococcosis.","date":"2020","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32426296","citation_count":9,"is_preprint":false},{"pmid":"17403055","id":"PMC_17403055","title":"Identification of a diagnostic antibody-binding region on the immunogenic protein EpC1 from Echinococcus granulosus and its application in population screening for cystic echinococcosis.","date":"2007","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17403055","citation_count":9,"is_preprint":false},{"pmid":"35863520","id":"PMC_35863520","title":"Evaluation of a novel Echinococcus granulosus recombinant fusion B-EpC1 antigen for the diagnosis of human cystic echinococcosis using indirect ELISA in comparison with a commercial diagnostic ELISA kit.","date":"2022","source":"Experimental parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/35863520","citation_count":9,"is_preprint":false},{"pmid":"23783398","id":"PMC_23783398","title":"Immunoproteomics approach for EPC1 antigenic epitope prediction of G1 and G6 strains of Echinococcus granulosus.","date":"2013","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/23783398","citation_count":8,"is_preprint":false},{"pmid":"29696723","id":"PMC_29696723","title":"Design and construction of a new recombinant fusion protein (2b2t+EPC1) and its assessment for serodiagnosis of cystic echinococcosis.","date":"2018","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/29696723","citation_count":8,"is_preprint":false},{"pmid":"38439957","id":"PMC_38439957","title":"EPC1/2 regulate hematopoietic stem and progenitor cell proliferation by modulating H3 acetylation and DLST.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38439957","citation_count":7,"is_preprint":false},{"pmid":"31700823","id":"PMC_31700823","title":"Design and Construction of a Fusion Peptide Containing B1, B2, B4, and EPC1 Epitopes for Diagnosis of Human Cystic Echinococcosis.","date":"2019","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/31700823","citation_count":6,"is_preprint":false},{"pmid":"25904943","id":"PMC_25904943","title":"Evaluation of Dot Immunogold Filtration Assay (DIGFA) By Recombinant Protein EPC1 for Anti- Echinococcus granulosus IgG Antibody.","date":"2015","source":"Iranian journal of parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/25904943","citation_count":5,"is_preprint":false},{"pmid":"34841830","id":"PMC_34841830","title":"Expression and Biological Functions of EPC1 in Nasopharyngeal Carcinoma.","date":"2021","source":"Archives of Iranian medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34841830","citation_count":2,"is_preprint":false},{"pmid":"21970102","id":"PMC_21970102","title":"[Cloning, expression and immunodiagnostic evaluation of antigen EPC1 from Echinococcus granulosus].","date":"2011","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21970102","citation_count":1,"is_preprint":false},{"pmid":"41670399","id":"PMC_41670399","title":"CCER1 condensates participate in histone-to-protamine transition by recruiting the TIP60/EPC1/NuA4 acetyltransferase complex.","date":"2026","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41670399","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21799,"output_tokens":2401,"usd":0.050706,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9452,"output_tokens":3521,"usd":0.067642,"stage2_stop_reason":"end_turn"},"total_usd":0.118348,"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\": 2004,\n      \"finding\": \"EPC1 was identified as a binding partner of transcriptional repressor E2F6 via yeast two-hybrid screen; E2F6, DP1, and EPC1 form a stable core complex with repressive activity both in vitro and in vivo; EPC1 also interacts with the proliferation-specific polycomb protein EZH2, and affinity purification showed E2F6, DP1, EPC1, EZH2, and Sin3B co-elute as a novel complex that exists only in proliferating cells.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, affinity purification/co-elution, cell-based repression assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal yeast two-hybrid plus in vitro and in vivo complex formation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15536069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EPC1 physically interacts with E2F1 (E2F1 binds the EPC1 promoter; EPC1 co-localizes with E2F1 in the nucleus); depletion of EPC1 potentiates E2F1-mediated apoptosis after genotoxic treatment and abolishes tumor cell motility; EPC1 modulates E2F1 transcriptional activity in a target-gene-specific manner, activating anti-apoptotic genes (BCL-2, Survivin/BIRC5) and silencing pro-apoptotic targets.\",\n      \"method\": \"ChIP, co-immunoprecipitation, nuclear co-localization, siRNA knockdown with apoptosis and motility readouts, reporter/gene expression assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, co-IP, KD phenotypes) in single lab\",\n      \"pmids\": [\"26350215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EPC1 and EPC2, as components of the EP400 complex, are required for the clonogenic and leukemia stem cell potential of MLL-mutated AML cells; EPC1/EPC2 knockdown induces apoptosis in murine MLL-AF9 AML cells and causes MYC protein accumulation; pharmacological inhibition of MYC:MAX dimerization or concomitant MYC knockdown reduces apoptosis following EPC1 KD, placing EPC1 upstream of MYC protein levels.\",\n      \"method\": \"Targeted shRNA knockdown screen, colony-forming assays, transplantation leukemia stem cell assay, transcriptional profiling, pharmacological MYC inhibition, epistasis by concomitant KD\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus functional phenotypic readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24166297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In yeast Piccolo NuA4 complex, the EPcA homology domain of Epl1 (ortholog of human EPC1) contains a short basic region at its N-terminus that is necessary for nucleosomal histone H4/H2A acetyltransferase activity; this basic region is positioned in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and nucleosomal DNA when Piccolo NuA4 is bound to the nucleosome, but is not required for nucleosome binding per se.\",\n      \"method\": \"In vitro nucleosomal histone acetyltransferase assay, site-directed mutagenesis, site-specific cross-linking proximity assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstituted HAT assay with mutagenesis and structural proximity mapping, multiple orthogonal methods\",\n      \"pmids\": [\"23109429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In S. cerevisiae, deletion of Epl1 (Enhancer of polycomb, ortholog of human EPC1) can be bypassed by loss of the Rpd3L deacetylase complex, a suppression property shared with the catalytic subunit Esa1; dissection of Epl1 domains shows distinct regions are required in vivo for interaction with specific NuA4 subunits, histone acetylation, and chromatin targeting, demonstrating that Epl1 promotes Esa1 catalytic activity through structural scaffolding.\",\n      \"method\": \"Genetic suppressor bypass screen, deletion mapping, in vivo histone acetylation assays, chromatin targeting assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus domain dissection and functional assays, single lab\",\n      \"pmids\": [\"28108589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the MBTD1–EPC1 complex revealed that a hydrophobic C-terminal fragment of EPC1 engages the MBT repeats of MBTD1 at a site distinct from the H4K20me-binding pocket; cellular assays validated key interface residues, establishing that EPC1 recruits MBTD1 into the NuA4/TIP60 complex to influence transcription and DNA repair pathway choice.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, cellular interaction assays (co-IP, functional readouts for DNA repair)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validated by multiple cellular assays in single rigorous study\",\n      \"pmids\": [\"32209463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EPC1 and EPC2 regulate hematopoietic stem and progenitor cell (HSPC) proliferation; depletion of EPC1/2 reduces HSPC numbers in the aorta-gonad mesonephros and caudal hematopoietic tissue by impairing proliferation; mechanistically, EPC1/2 regulate histone H3 acetylation and control expression of DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation, cooperating with transcription factors SRF and FOXR2.\",\n      \"method\": \"Morpholino/genetic knockdown in zebrafish, K562 cell knockdown, ChIP-based H3 acetylation assays, gene expression analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype plus chromatin (H3 acetylation) mechanistic readout, single lab\",\n      \"pmids\": [\"38439957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCER1 nuclear condensates recruit TIP60 and EPC1 subunits to the NuA4 acetyltransferase complex in spermatids; disruption of CCER1 droplets impairs TIP60–EPC1 interaction and reduces histone H4 hyperacetylation in nucleosomes, leading to defective DNA strand breakage and insufficient histone-to-protamine replacement during spermiogenesis.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (CCER1-Tag knock-in mice), co-IP validation, H4 acetylation assay, genetic knock-in/knockout in mice\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus co-IP validation and functional phenotypic readout in knock-in mouse model, single lab\",\n      \"pmids\": [\"41670399\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPC1 (Enhancer of Polycomb 1) is a non-catalytic scaffolding subunit of the NuA4/TIP60 histone acetyltransferase complex that uses its EPcA domain basic region to orient Esa1/TIP60 for nucleosomal H4/H2A acetylation, recruits MBTD1 into the complex via a hydrophobic C-terminal interface to regulate DNA repair pathway choice, forms a repressive complex with E2F6–DP1 and the proliferation-specific EZH2, modulates E2F1 transcriptional activity to promote anti-apoptotic gene expression and suppress DNA-damage-induced apoptosis, sustains MLL-leukemia stem cell potential partly by preventing aberrant MYC accumulation, and supports hematopoietic stem/progenitor cell proliferation through regulation of H3 acetylation and DLST expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPC1 (Enhancer of Polycomb 1) is a non-catalytic scaffolding subunit of the NuA4/TIP60 histone acetyltransferase complex that orients catalytic activity toward nucleosomal histones and couples it to specific chromatin outcomes [#3, #4]. In the yeast Piccolo NuA4 ortholog Epl1, a short basic region within the conserved EPcA domain is positioned near the H2A tail, the H4 globular region, and nucleosomal DNA, and is required for nucleosomal H4/H2A acetyltransferase activity without being needed for nucleosome binding, while distinct Epl1 domains mediate subunit interaction, histone acetylation, and chromatin targeting — establishing that EPC1 promotes Esa1/TIP60 catalysis through structural scaffolding [#3, #4]. A hydrophobic C-terminal fragment of EPC1 engages the MBT repeats of MBTD1 at a site distinct from the H4K20me-binding pocket, recruiting MBTD1 into the complex to influence transcription and DNA-repair pathway choice [#5]. Beyond its complex-assembly role, EPC1 acts in transcriptional control: it forms a proliferation-specific repressive complex with E2F6, DP1, EZH2, and Sin3B [#0], and modulates E2F1 activity in a target-specific manner, activating anti-apoptotic genes (BCL-2, BIRC5) while suppressing genotoxin-induced apoptosis and supporting tumor cell motility [#1]. In hematopoiesis, EPC1 (with EPC2) is required for MLL-rearranged leukemia stem cell potential, acting upstream of MYC protein levels to prevent aberrant MYC accumulation [#2], and sustains normal hematopoietic stem/progenitor proliferation by regulating H3 acetylation and DLST expression in cooperation with SRF and FOXR2 [#6]. EPC1 is also recruited with TIP60 by CCER1 nuclear condensates during spermiogenesis to drive H4 hyperacetylation needed for histone-to-protamine exchange [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established EPC1 as a partner of transcriptional repressors, placing it in a proliferation-specific repressive complex rather than acting only as a generic acetyltransferase subunit.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, affinity purification/co-elution and cell-based repression assays defining an E2F6\\u2013DP1\\u2013EPC1\\u2013EZH2\\u2013Sin3B complex\",\n      \"pmids\": [\"15536069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define which EPC1 region mediates these interactions\", \"Repressed target genes not directly enumerated\", \"Relationship to the NuA4/TIP60 complex not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the structural basis for how the EPcA domain promotes catalysis, showing the basic region orients the complex on the nucleosome for H4/H2A acetylation independent of nucleosome binding.\",\n      \"evidence\": \"In vitro reconstituted nucleosomal HAT assays with site-directed mutagenesis and site-specific cross-linking proximity mapping in yeast Piccolo NuA4 (Epl1 ortholog)\",\n      \"pmids\": [\"23109429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated in yeast Epl1, not human EPC1 directly\", \"Does not address full NuA4/TIP60 complex behavior\", \"Atomic-resolution structure not obtained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected EPC1 to disease-relevant biology by placing it upstream of MYC protein levels in MLL-leukemia stem cells.\",\n      \"evidence\": \"shRNA knockdown screen, colony-forming and transplantation leukemia stem cell assays, transcriptional profiling, and pharmacological/genetic MYC epistasis in murine MLL-AF9 AML\",\n      \"pmids\": [\"24166297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EPC1 limits MYC accumulation unresolved\", \"Chromatin/acetylation events at MYC not mapped\", \"Single-lab finding without orthogonal validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed EPC1 modulates E2F1 transcriptional output to bias cells toward survival, linking it to apoptosis suppression and tumor cell motility.\",\n      \"evidence\": \"ChIP, co-IP, nuclear co-localization, siRNA knockdown with apoptosis/motility readouts and reporter assays\",\n      \"pmids\": [\"26350215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NuA4/TIP60 acetyltransferase activity mediates target selectivity not shown\", \"Direct vs indirect regulation of pro/anti-apoptotic targets not fully resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated genetically that EPC1/Epl1 is functionally interchangeable with the catalytic subunit in promoting acetylation, formalizing its scaffolding role through domain dissection.\",\n      \"evidence\": \"Genetic suppressor bypass screen (Rpd3L loss), deletion mapping, and in vivo histone acetylation and chromatin targeting assays in S. cerevisiae\",\n      \"pmids\": [\"28108589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in yeast; human EPC1 domain assignments inferred\", \"Specific subunit-binding interfaces not structurally resolved here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how EPC1 recruits MBTD1 into NuA4/TIP60, providing a molecular handle linking complex composition to DNA-repair pathway choice.\",\n      \"evidence\": \"X-ray crystallography of the MBTD1\\u2013EPC1 complex with interface mutagenesis validated in cellular co-IP and DNA-repair readouts\",\n      \"pmids\": [\"32209463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative impact of MBTD1 recruitment on specific repair pathways not fully defined\", \"Interplay with the E2F1/E2F6 functions of EPC1 unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended EPC1 function to normal hematopoietic stem/progenitor proliferation, identifying DLST as an H3-acetylation-regulated target.\",\n      \"evidence\": \"Morpholino/genetic knockdown in zebrafish, K562 knockdown, ChIP-based H3 acetylation and gene expression analysis with SRF/FOXR2 cooperation\",\n      \"pmids\": [\"38439957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct EPC1 occupancy at the DLST locus not shown\", \"Mechanism of cooperation with SRF/FOXR2 unresolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed EPC1 is recruited by phase-separated CCER1 condensates with TIP60 to drive H4 hyperacetylation required for chromatin remodeling in spermiogenesis.\",\n      \"evidence\": \"IP-MS in CCER1-Tag knock-in mice, co-IP, H4 acetylation assays, and knock-in/knockout mouse phenotyping\",\n      \"pmids\": [\"41670399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CCER1\\u2013EPC1 contact vs indirect recruitment not distinguished\", \"Genomic targets of CCER1-directed acetylation not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EPC1's distinct activities — NuA4/TIP60 scaffolding, MBTD1 recruitment, E2F-family transcriptional regulation, and MYC restraint — are integrated within a single protein and coordinated across cell contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length human EPC1 within NuA4/TIP60\", \"Whether E2F6/E2F1 regulation requires acetyltransferase activity unknown\", \"Molecular link between EPC1 and MYC protein turnover undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"NuA4/TIP60 histone acetyltransferase complex\", \"Piccolo NuA4\", \"EP400 complex\", \"E2F6\\u2013DP1\\u2013EPC1\\u2013EZH2\\u2013Sin3B repressive complex\"],\n    \"partners\": [\"E2F6\", \"TFDP1\", \"EZH2\", \"SIN3B\", \"E2F1\", \"MBTD1\", \"EPC2\", \"CCER1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}