{"gene":"EPC2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2013,"finding":"EPC1 and EPC2 are required components of the EP400 histone acetyltransferase complex that sustain oncogenic potential in MLL-mutated AML; knockdown of EPC1 or EPC2 induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential, while sparing normal hematopoietic stem and progenitor cells. Mechanistically, EPC1/2 knockdown caused accumulation of MYC protein (increased MYC activity signature) in leukemic but not normal GMP cells, and pharmacological inhibition of MYC:MAX dimerization or concomitant MYC knockdown reduced apoptosis following EPC1 knockdown, linking EPC2/EP400 complex function to prevention of MYC accumulation.","method":"Targeted shRNA knockdown screen of chromatin regulatory genes; colony-forming assays; leukemia stem cell transplantation assays; gene expression profiling; pharmacological MYC:MAX inhibition; concomitant MYC knockdown rescue experiments","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional validation with multiple orthogonal approaches (KD screen, LSC assays, transcriptomics, pharmacologic rescue, genetic rescue) in both murine and human primary AML cells","pmids":["24166297"],"is_preprint":false},{"year":2017,"finding":"EPC (Enhancer of Polycomb) proteins, including EPC2, function as non-catalytic subunits of the NuA4/TIP60 histone acetyltransferase complex and are critical regulators of global and targeted histone acetylation. Studies in yeast (Epl1, the ortholog) demonstrated that EPC is as important for gene expression and histone acetylation as the catalytic subunit of NuA4, establishing EPC2's role as a key genomic regulator through its interaction with this acetyltransferase complex.","method":"Review synthesizing genetic and biochemical studies from yeast, Drosophila, and mammalian models; yeast Epl1 mutant analyses for histone acetylation and gene expression","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of replicated findings across organisms, but this is a review paper; underlying yeast data are strong but EPC2-specific mammalian mechanistic data are inferred from ortholog studies","pmids":["28884217"],"is_preprint":false},{"year":2024,"finding":"EPC1 and EPC2, as components of histone acetyltransferase/deacetylase complexes, regulate histone H3 acetylation and control hematopoietic stem and progenitor cell (HSPC) emergence and proliferation. Depletion of EPC1/2 in zebrafish significantly reduced HSPC numbers in the aorta-gonad-mesonephros and caudal hematopoietic tissue by impairing proliferation. Mechanistically, EPC1/2 regulate expression of DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation, and cooperate with transcription factors serum response factor (SRF) and FOXR2 to control HSPC emergence and proliferation, linking EPC2 to mitochondrial metabolism through DLST.","method":"EPC1/2 knockdown in zebrafish; HSPC counting in AGM and CHT regions; H3 acetylation assays in K562 cells; gene expression analysis; transcription factor co-regulation experiments with SRF and FOXR2","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish KD with defined cellular phenotype plus mechanistic follow-up in K562 cells; single lab with two orthogonal systems","pmids":["38439957"],"is_preprint":false},{"year":2018,"finding":"EPC2 forms an in-frame fusion transcript with PHF1 (EPC2-PHF1) in low-grade endometrial stromal sarcoma, identified by RNA sequencing and confirmed by RT-PCR, Sanger sequencing, and FISH. This represents a recurrent class of PHF1 rearrangements in LG-ESS involving Polycomb-related genes as fusion partners, analogous to previously described EPC1-PHF1 fusions.","method":"RNA sequencing; RT-PCR; Sanger sequencing; fluorescence in situ hybridization (FISH)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion confirmed by multiple orthogonal molecular methods (RNA-seq, RT-PCR, Sanger, FISH) in a single tumor case; no functional validation of fusion protein activity","pmids":["29721194"],"is_preprint":false},{"year":2021,"finding":"EPC2 participates in an in-frame gene fusion with GULP1 (EPC2-GULP1) in medulloblastoma. The fusion protein retains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 fused to the coiled-coil domain of GULP1. The fusion-derived neoantigen peptide was predicted to bind HLA-A*0201 and was able to induce a de novo CD8+ cytotoxic T cell response (characterized by interferon-gamma release) in vitro, demonstrating immunogenicity of the EPC2-GULP1 fusion.","method":"RNA-Seq identification; qRT-PCR validation in medulloblastoma samples; full-length sequence cloning; in silico HLA binding prediction; in vitro T cell stimulation assay measuring IFN-gamma release by CD8+ cytotoxic T cells","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fusion validated by RT-PCR across multiple samples, domain structure determined by cloning, immunogenicity confirmed by functional T cell assay; single lab, limited sample size","pmids":["34830991"],"is_preprint":false},{"year":2026,"finding":"EPC2, as a component of the NuA4 histone acetyltransferase complex, is recruited by the transcription factor NME2 to the Nlrp3 promoter in inflammasome-activated microglia. NME2 directly binds the Nlrp3 promoter and recruits EPC2, which induces H2AK5 acetylation and chromatin remodeling, thereby enhancing Nlrp3 transcription and promoting neuroinflammation in sepsis-associated encephalopathy. Conditional knockout of Nme2 in microglia significantly decreased IL-1β and attenuated cognitive impairment in septic mice.","method":"Single-cell RNA sequencing; chromatin immunoprecipitation (NME2 binding to Nlrp3 promoter); co-immunoprecipitation/interaction studies (NME2-EPC2 recruitment); H2AK5 acetylation assays; conditional Nme2 microglial knockout mice; pharmacological inhibition with stauprimide","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and recruitment of EPC2 demonstrated with ChIP, H2AK5 acetylation measured, functional validation by conditional KO in vivo; single lab, EPC2 role inferred from complex membership rather than direct EPC2 KO","pmids":["41713665"],"is_preprint":false}],"current_model":"EPC2 (Enhancer of Polycomb homolog 2) is a non-catalytic subunit of the NuA4/TIP60 histone acetyltransferase complex that regulates global and targeted histone H3 (and H2AK5) acetylation and chromatin remodeling; it is recruited to target gene promoters (e.g., Nlrp3) by transcription factors such as NME2, sustains oncogenic potential in MLL-mutated AML by preventing pathological MYC accumulation, regulates hematopoietic stem and progenitor cell proliferation through H3 acetylation-dependent control of DLST expression in cooperation with SRF and FOXR2, and is involved in chromosomal translocations generating oncogenic fusion proteins (EPC2-PHF1, EPC2-GULP1) in endometrial stromal sarcoma and medulloblastoma respectively."},"narrative":{"mechanistic_narrative":"EPC2 (Enhancer of Polycomb homolog 2) is a non-catalytic subunit of the NuA4/TIP60-type histone acetyltransferase complex that governs global and targeted histone acetylation to control gene expression in hematopoiesis, leukemia, and inflammation [PMID:28884217, PMID:24166297]. Studies of its yeast ortholog Epl1 established that the Enhancer-of-Polycomb subunit is as essential for histone acetylation and gene expression as the catalytic core of the complex, defining EPC2 as a core genomic regulator rather than an accessory factor [PMID:28884217]. In MLL-mutated AML, EPC2 (with EPC1) is a required component of the EP400 acetyltransferase complex that sustains leukemia stem cell potential by preventing pathological MYC protein accumulation, such that its loss triggers MYC-dependent apoptosis selectively in leukemic cells [PMID:24166297]. During development, EPC2 drives hematopoietic stem and progenitor cell emergence and proliferation by controlling DLST expression through H3 acetylation in cooperation with the transcription factors SRF and FOXR2, linking the complex to mitochondrial metabolism [PMID:38439957]. EPC2 is also recruited by the transcription factor NME2 to the Nlrp3 promoter in microglia, where it deposits H2AK5 acetylation to enhance inflammasome gene transcription [PMID:41713665]. Independently, EPC2 is recurrently involved in oncogenic gene fusions, forming in-frame EPC2-PHF1 transcripts in low-grade endometrial stromal sarcoma [PMID:29721194] and EPC2-GULP1 transcripts in medulloblastoma that retain its N-terminal EPcA domain and generate an immunogenic neoantigen [PMID:34830991].","teleology":[{"year":2013,"claim":"Established that EPC2 is functionally required to maintain leukemia and identified the mechanism as restraint of MYC, addressing whether this chromatin subunit had a non-redundant oncogenic role.","evidence":"shRNA knockdown screen, leukemia stem cell transplantation, transcriptomics, and pharmacologic/genetic MYC rescue in murine and human MLL-AML cells","pmids":["24166297"],"confidence":"High","gaps":["Does not define how the EP400/EPC2 complex mechanistically prevents MYC protein accumulation","Selectivity for leukemic over normal cells not explained at the chromatin level","No structural mapping of EPC2 within the EP400 complex"]},{"year":2017,"claim":"Framed EPC2 as a non-catalytic but essential NuA4/TIP60 subunit, answering whether the Enhancer-of-Polycomb protein contributes to acetylation beyond scaffolding.","evidence":"Review synthesizing yeast Epl1 mutant analyses of histone acetylation and gene expression across organisms","pmids":["28884217"],"confidence":"Medium","gaps":["Mammalian EPC2-specific mechanistic data inferred from yeast ortholog","Direct biochemical role of EPC2 in human complex acetyltransferase activity not shown","No demonstration of which histone marks EPC2 directs in mammals here"]},{"year":2018,"claim":"Showed EPC2 is a recurrent fusion partner in endometrial stromal sarcoma, extending Polycomb-related gene rearrangements beyond EPC1-PHF1.","evidence":"RNA sequencing with RT-PCR, Sanger sequencing, and FISH confirmation in a tumor case","pmids":["29721194"],"confidence":"Medium","gaps":["No functional validation of the EPC2-PHF1 fusion protein activity","Single tumor case","Oncogenic mechanism of the fusion not established"]},{"year":2021,"claim":"Defined the domain architecture and immunogenicity of an EPC2-GULP1 fusion in medulloblastoma, raising its potential as a neoantigen.","evidence":"RNA-Seq, qRT-PCR, full-length cloning, in silico HLA binding prediction, and in vitro CD8+ T cell IFN-gamma assay","pmids":["34830991"],"confidence":"Medium","gaps":["Transforming activity of the fusion protein not tested","Limited sample size and single lab","In vivo immunogenicity not demonstrated"]},{"year":2024,"claim":"Connected EPC2 to developmental hematopoiesis, showing it controls HSPC proliferation via H3-acetylation-dependent DLST expression and cofactor cooperation.","evidence":"EPC1/2 knockdown in zebrafish with HSPC counting, plus H3 acetylation and gene expression assays in K562 cells and SRF/FOXR2 co-regulation experiments","pmids":["38439957"],"confidence":"Medium","gaps":["EPC2-specific contribution not separated from EPC1","Mechanism of cooperation with SRF and FOXR2 not resolved","Single lab using two orthogonal systems"]},{"year":2026,"claim":"Demonstrated targeted recruitment of EPC2 to a specific promoter by a transcription factor, linking it to H2AK5 acetylation and inflammatory gene induction.","evidence":"scRNA-seq, ChIP for NME2 promoter binding, co-IP for NME2-EPC2 interaction, H2AK5 acetylation assays, and conditional Nme2 microglial knockout mice","pmids":["41713665"],"confidence":"Medium","gaps":["EPC2 role inferred from complex membership rather than direct EPC2 knockout","Whether NME2 recruits the full NuA4 complex or EPC2 alone is unresolved","Reciprocal validation of the NME2-EPC2 interaction limited"]},{"year":null,"claim":"How EPC2 selects target genes across distinct cellular contexts and whether its fusion proteins are transforming remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of EPC2 within human acetyltransferase complexes","Functional oncogenicity of EPC2-PHF1 and EPC2-GULP1 fusions untested","Rules governing transcription-factor-directed recruitment of EPC2 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5]}],"complexes":["NuA4/TIP60 histone acetyltransferase complex","EP400 complex"],"partners":["EPC1","NME2","SRF","FOXR2","PHF1","GULP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q52LR7","full_name":"Enhancer of polycomb homolog 2","aliases":["EPC-like"],"length_aa":807,"mass_kda":91.1,"function":"May play a role in transcription or DNA repair","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q52LR7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EPC2","classification":"Not Classified","n_dependent_lines":385,"n_total_lines":1208,"dependency_fraction":0.31870860927152317},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":4.0},{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPC2","total_profiled":1310},"omim":[{"mim_id":"611000","title":"ENHANCER OF POLYCOMB HOMOLOG 2; EPC2","url":"https://www.omim.org/entry/611000"},{"mim_id":"601409","title":"LYSINE ACETYLTRANSFERASE 5; KAT5","url":"https://www.omim.org/entry/601409"},{"mim_id":"156200","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 1; MRD1","url":"https://www.omim.org/entry/156200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EPC2"},"hgnc":{"alias_symbol":["DKFZP566F2124"],"prev_symbol":[]},"alphafold":{"accession":"Q52LR7","domains":[{"cath_id":"-","chopping":"434-482","consensus_level":"medium","plddt":74.9047,"start":434,"end":482},{"cath_id":"1.10.150","chopping":"104-185","consensus_level":"high","plddt":87.8804,"start":104,"end":185},{"cath_id":"1.20.5","chopping":"230-281","consensus_level":"high","plddt":95.7425,"start":230,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q52LR7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q52LR7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q52LR7-F1-predicted_aligned_error_v6.png","plddt_mean":57.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPC2","jax_strain_url":"https://www.jax.org/strain/search?query=EPC2"},"sequence":{"accession":"Q52LR7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q52LR7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q52LR7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q52LR7"}},"corpus_meta":[{"pmid":"12939398","id":"PMC_12939398","title":"Telomerase 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gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30841855","citation_count":12,"is_preprint":false},{"pmid":"32543665","id":"PMC_32543665","title":"HSV-1 Hijacks the Host DNA Damage Response in Corneal Epithelial Cells through ICP4-Mediated Activation of ATM.","date":"2020","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/32543665","citation_count":12,"is_preprint":false},{"pmid":"26396976","id":"PMC_26396976","title":"Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins.","date":"2015","source":"Virusdisease","url":"https://pubmed.ncbi.nlm.nih.gov/26396976","citation_count":12,"is_preprint":false},{"pmid":"29086334","id":"PMC_29086334","title":"Response to TNF-α Is Increasing Along with the Progression in Barrett's Esophagus.","date":"2017","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29086334","citation_count":11,"is_preprint":false},{"pmid":"22659271","id":"PMC_22659271","title":"2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features.","date":"2012","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22659271","citation_count":10,"is_preprint":false},{"pmid":"31539213","id":"PMC_31539213","title":"The emergence of zoonotic Fusarium oxysporum infection in captive-reared fingerlings of golden mahseer, Tor putitora (Hamilton, 1822) from the central Himalayan region of India.","date":"2019","source":"Transboundary and emerging diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31539213","citation_count":10,"is_preprint":false},{"pmid":"32222541","id":"PMC_32222541","title":"Forced expression of HOXA13 confers oncogenic hallmarks to esophageal keratinocytes.","date":"2020","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/32222541","citation_count":9,"is_preprint":false},{"pmid":"28884217","id":"PMC_28884217","title":"Critical genomic regulation mediated by Enhancer of Polycomb.","date":"2017","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28884217","citation_count":9,"is_preprint":false},{"pmid":"39209164","id":"PMC_39209164","title":"Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis.","date":"2024","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39209164","citation_count":7,"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":"34199909","id":"PMC_34199909","title":"Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34199909","citation_count":7,"is_preprint":false},{"pmid":"37266415","id":"PMC_37266415","title":"Effects of Replacing Fish Meal with Enzymatic Cottonseed Protein on the Growth Performance, Immunity, Antioxidation, and Intestinal Health of Chinese Soft-Shelled Turtle (Pelodiscus sinensis).","date":"2023","source":"Aquaculture nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/37266415","citation_count":7,"is_preprint":false},{"pmid":"34830991","id":"PMC_34830991","title":"Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34830991","citation_count":6,"is_preprint":false},{"pmid":"20298176","id":"PMC_20298176","title":"Modelling Barrett's oesophagus.","date":"2010","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/20298176","citation_count":6,"is_preprint":false},{"pmid":"39334892","id":"PMC_39334892","title":"Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39334892","citation_count":6,"is_preprint":false},{"pmid":"25988649","id":"PMC_25988649","title":"A novel interstitial deletion of 2q22.3 q23.3 in a patient with dysmorphic features, epilepsy, aganglionosis, pure red cell aplasia, and skeletal malformations.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25988649","citation_count":6,"is_preprint":false},{"pmid":"38111058","id":"PMC_38111058","title":"Absolute quantification of DNA damage response proteins.","date":"2023","source":"Genes and environment : the official journal of the Japanese Environmental Mutagen Society","url":"https://pubmed.ncbi.nlm.nih.gov/38111058","citation_count":4,"is_preprint":false},{"pmid":"40976365","id":"PMC_40976365","title":"Resolution of epithelial dysfunction in eosinophilic esophagitis is mediated by an HIF-1α-CD73-adenosine signaling axis.","date":"2025","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40976365","citation_count":3,"is_preprint":false},{"pmid":"39466790","id":"PMC_39466790","title":"Non-genetic differences underlie variability in proliferation among esophageal epithelial clones.","date":"2024","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/39466790","citation_count":3,"is_preprint":false},{"pmid":"27706612","id":"PMC_27706612","title":"Activation of Src tyrosine kinase in esophageal carcinoma cells in different regulatory environments and corresponding occurrence mechanism.","date":"2016","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/27706612","citation_count":3,"is_preprint":false},{"pmid":"39888001","id":"PMC_39888001","title":"Two homologous Zn2Cys6 transcription factors play crucial roles in host specificity of Colletotrichum orbiculare by controlling the expression of cucurbit-specific virulence effectors.","date":"2025","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/39888001","citation_count":2,"is_preprint":false},{"pmid":"39766266","id":"PMC_39766266","title":"Lysyl Oxidase Mediates Proliferation and Differentiation in the Esophageal Epithelium.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39766266","citation_count":1,"is_preprint":false},{"pmid":"20734129","id":"PMC_20734129","title":"Neuroprotective effects of active ingredients isolated from Pegasus laternarius on cultured cerebral neurons.","date":"2010","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/20734129","citation_count":1,"is_preprint":false},{"pmid":"41713665","id":"PMC_41713665","title":"NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy.","date":"2026","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/41713665","citation_count":0,"is_preprint":false},{"pmid":"41639242","id":"PMC_41639242","title":"Gene variants in the pheromone vomeronasal receptors and QTLs around behavioral and fat metabolism genes associated with altered feed efficiency in cattle.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41639242","citation_count":0,"is_preprint":false},{"pmid":"38826379","id":"PMC_38826379","title":"Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38826379","citation_count":0,"is_preprint":false},{"pmid":"42003098","id":"PMC_42003098","title":"Identification of Drug-resistant Cell Subpopulations in Colorectal Cancer Through Single-cell Analysis and Exploration of Potential Therapeutic Strategies.","date":"2026","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42003098","citation_count":0,"is_preprint":false},{"pmid":"42123694","id":"PMC_42123694","title":"Multiomics Reveals IL-17 Drives Epithelial Keratinization and Proliferation via EHF in Odontogenic Keratocysts.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42123694","citation_count":0,"is_preprint":false},{"pmid":"31055822","id":"PMC_31055822","title":"[Phenotypic and genotypic analysis of a girl carrying a 2q22.3 microduplication encompassing the MBD5 gene].","date":"2019","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31055822","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43472,"output_tokens":2604,"usd":0.084738,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9297,"output_tokens":2747,"usd":0.05758,"stage2_stop_reason":"end_turn"},"total_usd":0.142318,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers that describe mechanistic findings specifically about the EPC2 protein (Enhancer of Polycomb homolog 2, HGNC alias DKFZP566F2124).\n\nKey papers to assess:\n- Paper [22]: Direct mechanistic study of EPC1/EPC2 in AML leukemia stem cells - INCLUDE\n- Paper [52]: Review of EPC biology in model organisms - INCLUDE (mechanistic context)\n- Paper [54]: EPC1/2 in hematopoietic stem cells, H3 acetylation, DLST - INCLUDE\n- Paper [68]: NME2 recruits EPC2 to induce H2AK5 acetylation at Nlrp3 promoter - INCLUDE\n- Paper [21]: EPC2-PHF1 fusion transcript in LG-ESS - INCLUDE (structural/fusion finding)\n- Paper [57]: EPC2-GULP1 fusion in medulloblastoma, domain characterization - INCLUDE\n- Papers [1,3-20, 23-51, 53, 55-56, 58-67, 69-73]: Mostly use EPC2 as a cell line name (esophageal epithelial cell line), are GWAS/deletion syndrome papers, or are symbol collisions. EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"EPC1 and EPC2 are required components of the EP400 histone acetyltransferase complex that sustain oncogenic potential in MLL-mutated AML; knockdown of EPC1 or EPC2 induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential, while sparing normal hematopoietic stem and progenitor cells. Mechanistically, EPC1/2 knockdown caused accumulation of MYC protein (increased MYC activity signature) in leukemic but not normal GMP cells, and pharmacological inhibition of MYC:MAX dimerization or concomitant MYC knockdown reduced apoptosis following EPC1 knockdown, linking EPC2/EP400 complex function to prevention of MYC accumulation.\",\n      \"method\": \"Targeted shRNA knockdown screen of chromatin regulatory genes; colony-forming assays; leukemia stem cell transplantation assays; gene expression profiling; pharmacological MYC:MAX inhibition; concomitant MYC knockdown rescue experiments\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional validation with multiple orthogonal approaches (KD screen, LSC assays, transcriptomics, pharmacologic rescue, genetic rescue) in both murine and human primary AML cells\",\n      \"pmids\": [\"24166297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EPC (Enhancer of Polycomb) proteins, including EPC2, function as non-catalytic subunits of the NuA4/TIP60 histone acetyltransferase complex and are critical regulators of global and targeted histone acetylation. Studies in yeast (Epl1, the ortholog) demonstrated that EPC is as important for gene expression and histone acetylation as the catalytic subunit of NuA4, establishing EPC2's role as a key genomic regulator through its interaction with this acetyltransferase complex.\",\n      \"method\": \"Review synthesizing genetic and biochemical studies from yeast, Drosophila, and mammalian models; yeast Epl1 mutant analyses for histone acetylation and gene expression\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of replicated findings across organisms, but this is a review paper; underlying yeast data are strong but EPC2-specific mammalian mechanistic data are inferred from ortholog studies\",\n      \"pmids\": [\"28884217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EPC1 and EPC2, as components of histone acetyltransferase/deacetylase complexes, regulate histone H3 acetylation and control hematopoietic stem and progenitor cell (HSPC) emergence and proliferation. Depletion of EPC1/2 in zebrafish significantly reduced HSPC numbers in the aorta-gonad-mesonephros and caudal hematopoietic tissue by impairing proliferation. Mechanistically, EPC1/2 regulate expression of DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation, and cooperate with transcription factors serum response factor (SRF) and FOXR2 to control HSPC emergence and proliferation, linking EPC2 to mitochondrial metabolism through DLST.\",\n      \"method\": \"EPC1/2 knockdown in zebrafish; HSPC counting in AGM and CHT regions; H3 acetylation assays in K562 cells; gene expression analysis; transcription factor co-regulation experiments with SRF and FOXR2\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish KD with defined cellular phenotype plus mechanistic follow-up in K562 cells; single lab with two orthogonal systems\",\n      \"pmids\": [\"38439957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EPC2 forms an in-frame fusion transcript with PHF1 (EPC2-PHF1) in low-grade endometrial stromal sarcoma, identified by RNA sequencing and confirmed by RT-PCR, Sanger sequencing, and FISH. This represents a recurrent class of PHF1 rearrangements in LG-ESS involving Polycomb-related genes as fusion partners, analogous to previously described EPC1-PHF1 fusions.\",\n      \"method\": \"RNA sequencing; RT-PCR; Sanger sequencing; fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion confirmed by multiple orthogonal molecular methods (RNA-seq, RT-PCR, Sanger, FISH) in a single tumor case; no functional validation of fusion protein activity\",\n      \"pmids\": [\"29721194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EPC2 participates in an in-frame gene fusion with GULP1 (EPC2-GULP1) in medulloblastoma. The fusion protein retains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 fused to the coiled-coil domain of GULP1. The fusion-derived neoantigen peptide was predicted to bind HLA-A*0201 and was able to induce a de novo CD8+ cytotoxic T cell response (characterized by interferon-gamma release) in vitro, demonstrating immunogenicity of the EPC2-GULP1 fusion.\",\n      \"method\": \"RNA-Seq identification; qRT-PCR validation in medulloblastoma samples; full-length sequence cloning; in silico HLA binding prediction; in vitro T cell stimulation assay measuring IFN-gamma release by CD8+ cytotoxic T cells\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fusion validated by RT-PCR across multiple samples, domain structure determined by cloning, immunogenicity confirmed by functional T cell assay; single lab, limited sample size\",\n      \"pmids\": [\"34830991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EPC2, as a component of the NuA4 histone acetyltransferase complex, is recruited by the transcription factor NME2 to the Nlrp3 promoter in inflammasome-activated microglia. NME2 directly binds the Nlrp3 promoter and recruits EPC2, which induces H2AK5 acetylation and chromatin remodeling, thereby enhancing Nlrp3 transcription and promoting neuroinflammation in sepsis-associated encephalopathy. Conditional knockout of Nme2 in microglia significantly decreased IL-1β and attenuated cognitive impairment in septic mice.\",\n      \"method\": \"Single-cell RNA sequencing; chromatin immunoprecipitation (NME2 binding to Nlrp3 promoter); co-immunoprecipitation/interaction studies (NME2-EPC2 recruitment); H2AK5 acetylation assays; conditional Nme2 microglial knockout mice; pharmacological inhibition with stauprimide\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and recruitment of EPC2 demonstrated with ChIP, H2AK5 acetylation measured, functional validation by conditional KO in vivo; single lab, EPC2 role inferred from complex membership rather than direct EPC2 KO\",\n      \"pmids\": [\"41713665\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPC2 (Enhancer of Polycomb homolog 2) is a non-catalytic subunit of the NuA4/TIP60 histone acetyltransferase complex that regulates global and targeted histone H3 (and H2AK5) acetylation and chromatin remodeling; it is recruited to target gene promoters (e.g., Nlrp3) by transcription factors such as NME2, sustains oncogenic potential in MLL-mutated AML by preventing pathological MYC accumulation, regulates hematopoietic stem and progenitor cell proliferation through H3 acetylation-dependent control of DLST expression in cooperation with SRF and FOXR2, and is involved in chromosomal translocations generating oncogenic fusion proteins (EPC2-PHF1, EPC2-GULP1) in endometrial stromal sarcoma and medulloblastoma respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EPC2 (Enhancer of Polycomb homolog 2) is a non-catalytic subunit of the NuA4/TIP60-type histone acetyltransferase complex that governs global and targeted histone acetylation to control gene expression in hematopoiesis, leukemia, and inflammation [#1, #0]. Studies of its yeast ortholog Epl1 established that the Enhancer-of-Polycomb subunit is as essential for histone acetylation and gene expression as the catalytic core of the complex, defining EPC2 as a core genomic regulator rather than an accessory factor [#1]. In MLL-mutated AML, EPC2 (with EPC1) is a required component of the EP400 acetyltransferase complex that sustains leukemia stem cell potential by preventing pathological MYC protein accumulation, such that its loss triggers MYC-dependent apoptosis selectively in leukemic cells [#0]. During development, EPC2 drives hematopoietic stem and progenitor cell emergence and proliferation by controlling DLST expression through H3 acetylation in cooperation with the transcription factors SRF and FOXR2, linking the complex to mitochondrial metabolism [#2]. EPC2 is also recruited by the transcription factor NME2 to the Nlrp3 promoter in microglia, where it deposits H2AK5 acetylation to enhance inflammasome gene transcription [#5]. Independently, EPC2 is recurrently involved in oncogenic gene fusions, forming in-frame EPC2-PHF1 transcripts in low-grade endometrial stromal sarcoma [#3] and EPC2-GULP1 transcripts in medulloblastoma that retain its N-terminal EPcA domain and generate an immunogenic neoantigen [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that EPC2 is functionally required to maintain leukemia and identified the mechanism as restraint of MYC, addressing whether this chromatin subunit had a non-redundant oncogenic role.\",\n      \"evidence\": \"shRNA knockdown screen, leukemia stem cell transplantation, transcriptomics, and pharmacologic/genetic MYC rescue in murine and human MLL-AML cells\",\n      \"pmids\": [\"24166297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not define how the EP400/EPC2 complex mechanistically prevents MYC protein accumulation\",\n        \"Selectivity for leukemic over normal cells not explained at the chromatin level\",\n        \"No structural mapping of EPC2 within the EP400 complex\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Framed EPC2 as a non-catalytic but essential NuA4/TIP60 subunit, answering whether the Enhancer-of-Polycomb protein contributes to acetylation beyond scaffolding.\",\n      \"evidence\": \"Review synthesizing yeast Epl1 mutant analyses of histone acetylation and gene expression across organisms\",\n      \"pmids\": [\"28884217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mammalian EPC2-specific mechanistic data inferred from yeast ortholog\",\n        \"Direct biochemical role of EPC2 in human complex acetyltransferase activity not shown\",\n        \"No demonstration of which histone marks EPC2 directs in mammals here\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed EPC2 is a recurrent fusion partner in endometrial stromal sarcoma, extending Polycomb-related gene rearrangements beyond EPC1-PHF1.\",\n      \"evidence\": \"RNA sequencing with RT-PCR, Sanger sequencing, and FISH confirmation in a tumor case\",\n      \"pmids\": [\"29721194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional validation of the EPC2-PHF1 fusion protein activity\",\n        \"Single tumor case\",\n        \"Oncogenic mechanism of the fusion not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the domain architecture and immunogenicity of an EPC2-GULP1 fusion in medulloblastoma, raising its potential as a neoantigen.\",\n      \"evidence\": \"RNA-Seq, qRT-PCR, full-length cloning, in silico HLA binding prediction, and in vitro CD8+ T cell IFN-gamma assay\",\n      \"pmids\": [\"34830991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Transforming activity of the fusion protein not tested\",\n        \"Limited sample size and single lab\",\n        \"In vivo immunogenicity not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected EPC2 to developmental hematopoiesis, showing it controls HSPC proliferation via H3-acetylation-dependent DLST expression and cofactor cooperation.\",\n      \"evidence\": \"EPC1/2 knockdown in zebrafish with HSPC counting, plus H3 acetylation and gene expression assays in K562 cells and SRF/FOXR2 co-regulation experiments\",\n      \"pmids\": [\"38439957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"EPC2-specific contribution not separated from EPC1\",\n        \"Mechanism of cooperation with SRF and FOXR2 not resolved\",\n        \"Single lab using two orthogonal systems\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated targeted recruitment of EPC2 to a specific promoter by a transcription factor, linking it to H2AK5 acetylation and inflammatory gene induction.\",\n      \"evidence\": \"scRNA-seq, ChIP for NME2 promoter binding, co-IP for NME2-EPC2 interaction, H2AK5 acetylation assays, and conditional Nme2 microglial knockout mice\",\n      \"pmids\": [\"41713665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"EPC2 role inferred from complex membership rather than direct EPC2 knockout\",\n        \"Whether NME2 recruits the full NuA4 complex or EPC2 alone is unresolved\",\n        \"Reciprocal validation of the NME2-EPC2 interaction limited\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EPC2 selects target genes across distinct cellular contexts and whether its fusion proteins are transforming remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of EPC2 within human acetyltransferase complexes\",\n        \"Functional oncogenicity of EPC2-PHF1 and EPC2-GULP1 fusions untested\",\n        \"Rules governing transcription-factor-directed recruitment of EPC2 unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"complexes\": [\"NuA4/TIP60 histone acetyltransferase complex\", \"EP400 complex\"],\n    \"partners\": [\"EPC1\", \"NME2\", \"SRF\", \"FOXR2\", \"PHF1\", \"GULP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":6,"faith_pct":66.66666666666667}}