Affinage

EPC2

Enhancer of polycomb homolog 2 · UniProt Q52LR7

Length
807 aa
Mass
91.1 kDa
Annotated
2026-06-09
73 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge faithfulness: 4/6 claims corpus-supported (67%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 High

    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

    PMID:24166297

    Open questions at the time
    • 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
  2. 2017 Medium

    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

    PMID:28884217

    Open questions at the time
    • 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
  3. 2018 Medium

    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

    PMID:29721194

    Open questions at the time
    • No functional validation of the EPC2-PHF1 fusion protein activity
    • Single tumor case
    • Oncogenic mechanism of the fusion not established
  4. 2021 Medium

    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

    PMID:34830991

    Open questions at the time
    • Transforming activity of the fusion protein not tested
    • Limited sample size and single lab
    • In vivo immunogenicity not demonstrated
  5. 2024 Medium

    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

    PMID:38439957

    Open questions at the time
    • EPC2-specific contribution not separated from EPC1
    • Mechanism of cooperation with SRF and FOXR2 not resolved
    • Single lab using two orthogonal systems
  6. 2026 Medium

    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

    PMID:41713665

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EPC2 selects target genes across distinct cellular contexts and whether its fusion proteins are transforming remain unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
EPC1FOXR2GULP1NME2PHF1SRF
Complex memberships
EP400 complexNuA4/TIP60 histone acetyltransferase complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. 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 Leukemia High 24166297
2017 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. Review synthesizing genetic and biochemical studies from yeast, Drosophila, and mammalian models; yeast Epl1 mutant analyses for histone acetylation and gene expression Current genetics Medium 28884217
2024 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. 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 iScience Medium 38439957
2018 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. RNA sequencing; RT-PCR; Sanger sequencing; fluorescence in situ hybridization (FISH) Oncotarget Medium 29721194
2021 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. 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 Cancers Medium 34830991
2026 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. 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 Brain, behavior, and immunity Medium 41713665

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Telomerase induces immortalization of human esophageal keratinocytes without p16INK4a inactivation. Molecular cancer research : MCR 184 12939398
2010 Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology 178 21123754
2011 AFM stiffness nanotomography of normal, metaplastic and dysplastic human esophageal cells. Physical biology 116 21301067
2009 Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis. Carcinogenesis 107 20042640
2022 Detergent exposure induces epithelial barrier dysfunction and eosinophilic inflammation in the esophagus. Allergy 79 35899466
2017 Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis. The Journal of allergy and clinical immunology 79 28104354
2009 Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. European journal of human genetics : EJHG 71 19904302
2009 The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. European journal of human genetics : EJHG 67 19809484
2010 Insulin-like growth factor-binding protein-3 promotes transforming growth factor-{beta}1-mediated epithelial-to-mesenchymal transition and motility in transformed human esophageal cells. Carcinogenesis 66 20513670
2017 TGF-β1 alters esophageal epithelial barrier function by attenuation of claudin-7 in eosinophilic esophagitis. Mucosal immunology 65 28832026
2012 Esophageal epithelial and mesenchymal cross-talk leads to features of epithelial to mesenchymal transition in vitro. Experimental cell research 64 23237990
2021 Butyrate and propionate restore interleukin 13-compromised esophageal epithelial barrier function. Allergy 62 34458999
2008 Structural, magnetic, electrochemical, catalytic, DNA binding and cleavage studies of new macrocyclic binuclear copper(II) complexes. Journal of inorganic biochemistry 60 19187967
2009 TLR3-mediated NF-{kappa}B signaling in human esophageal epithelial cells. American journal of physiology. Gastrointestinal and liver physiology 50 19779021
2014 Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition. Experimental cell research 45 25183431
2008 2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features? Journal of medical genetics 45 18812405
2016 Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE). PloS one 42 26992000
2019 Identification of anoctamin 1 (ANO1) as a key driver of esophageal epithelial proliferation in eosinophilic esophagitis. The Journal of allergy and clinical immunology 39 31647967
2006 Tumorigenic conversion of primary human esophageal epithelial cells using oncogene combinations in the absence of exogenous Ras. Cancer research 37 17079462
2018 17β-Estradiol protects the esophageal epithelium from IL-13-induced barrier dysfunction and remodeling. The Journal of allergy and clinical immunology 35 30578870
2018 Identification of an EPC2-PHF1 fusion transcript in low-grade endometrial stromal sarcoma. Oncotarget 34 29721194
2014 Comprehensive exploration of novel chimeric transcripts in clear cell renal cell carcinomas using whole transcriptome analysis. Genes, chromosomes & cancer 33 25230976
2013 Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells. Leukemia 33 24166297
2012 Development and characterization of an organotypic model of Barrett's esophagus. Journal of cellular physiology 30 21882191
2011 Severe intellectual disability and autistic features associated with microduplication 2q23.1. European journal of human genetics : EJHG 30 22085900
2023 IL-13-induced STAT3-dependent signaling networks regulate esophageal epithelial proliferation in eosinophilic esophagitis. The Journal of allergy and clinical immunology 26 37652141
2017 Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells. Journal of experimental & clinical cancer research : CR 26 28764725
2020 A novel MBTD1-PHF1 gene fusion in endometrial stromal sarcoma: A case report and literature review. Genes, chromosomes & cancer 25 32237188
2018 Solute carrier family 9, subfamily A, member 3 (SLC9A3)/sodium-hydrogen exchanger member 3 (NHE3) dysregulation and dilated intercellular spaces in patients with eosinophilic esophagitis. The Journal of allergy and clinical immunology 25 29729938
2014 Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis. American journal of physiology. Gastrointestinal and liver physiology 25 24481601
2011 Toll-like receptor 3 signaling enables human esophageal epithelial cells to sense endogenous danger signals released by necrotic cells. American journal of physiology. Gastrointestinal and liver physiology 25 21474651
2011 Clinical impact of HAb18G/CD147 expression in esophageal squamous cell carcinoma. Digestive diseases and sciences 23 21789540
2020 Autophagy mitigates ethanol-induced mitochondrial dysfunction and oxidative stress in esophageal keratinocytes. PloS one 21 32966340
2015 Cyanobacterial distributions along a physico-chemical gradient in the Northeastern Pacific Ocean. Environmental microbiology 21 25522910
2022 Heterozygosity and homozygosity regions affect reproductive success and the loss of reproduction: A case study with litter traits in pigs. Computational and structural biotechnology journal 20 35983229
2008 Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine. Human mutation 17 18330920
2009 Combined expression patterns of QTL-linked candidate genes best predict thermotolerance in Drosophila melanogaster. Journal of insect physiology 16 19651134
2020 Molecular Profile of Barrett's Esophagus and Gastroesophageal Reflux Disease in the Development of Translational Physiological and Pharmacological Studies. International journal of molecular sciences 15 32899384
2015 Wnt/β-Catenin Signaling Activation beyond Robust Nuclear β-Catenin Accumulation in Nondysplastic Barrett's Esophagus: Regulation via Dickkopf-1. Neoplasia (New York, N.Y.) 15 26297437
2011 An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition. BMC cancer 15 22026449
2011 2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features. European journal of medical genetics 15 22085995
2012 Heavy ions can enhance TGFβ mediated epithelial to mesenchymal transition. Journal of radiation research 14 22302045
2024 Phonon modes and electron-phonon coupling at the FeSe/SrTiO3 interface. Nature 13 39478222
2023 HPV16 infection promotes the malignant transformation of the esophagus and progression of esophageal squamous cell carcinoma. Journal of medical virology 12 37792307
2020 HSV-1 Hijacks the Host DNA Damage Response in Corneal Epithelial Cells through ICP4-Mediated Activation of ATM. Investigative ophthalmology & visual science 12 32543665
2019 In-depth characterization of the Wnt-signaling/β-catenin pathway in an in vitro model of Barrett's sequence. BMC gastroenterology 12 30841855
2015 Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins. Virusdisease 12 26396976
2017 Response to TNF-α Is Increasing Along with the Progression in Barrett's Esophagus. Digestive diseases and sciences 11 29086334
2019 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. Transboundary and emerging diseases 10 31539213
2012 2q23.1 microdeletion of the MBD5 gene in a female with seizures, developmental delay and distinct dysmorphic features. European journal of medical genetics 10 22659271
2020 Forced expression of HOXA13 confers oncogenic hallmarks to esophageal keratinocytes. Biochimica et biophysica acta. Molecular basis of disease 9 32222541
2017 Critical genomic regulation mediated by Enhancer of Polycomb. Current genetics 9 28884217
2024 EPC1/2 regulate hematopoietic stem and progenitor cell proliferation by modulating H3 acetylation and DLST. iScience 7 38439957
2024 Metabolic dysfunction mediated by HIF-1α contributes to epithelial differentiation defects in eosinophilic esophagitis. The Journal of allergy and clinical immunology 7 39209164
2023 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). Aquaculture nutrition 7 37266415
2021 Nrf2/Keap1-Pathway Activation and Reduced Susceptibility to Chemotherapy Treatment by Acidification in Esophageal Adenocarcinoma Cells. Cancers 7 34199909
2024 Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids. Biomolecules 6 39334892
2021 Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1. Cancers 6 34830991
2015 A novel interstitial deletion of 2q22.3 q23.3 in a patient with dysmorphic features, epilepsy, aganglionosis, pure red cell aplasia, and skeletal malformations. American journal of medical genetics. Part A 6 25988649
2010 Modelling Barrett's oesophagus. Biochemical Society transactions 6 20298176
2023 Absolute quantification of DNA damage response proteins. Genes and environment : the official journal of the Japanese Environmental Mutagen Society 4 38111058
2025 Resolution of epithelial dysfunction in eosinophilic esophagitis is mediated by an HIF-1α-CD73-adenosine signaling axis. The Journal of allergy and clinical immunology 3 40976365
2024 Non-genetic differences underlie variability in proliferation among esophageal epithelial clones. PLoS computational biology 3 39466790
2016 Activation of Src tyrosine kinase in esophageal carcinoma cells in different regulatory environments and corresponding occurrence mechanism. Genetics and molecular research : GMR 3 27706612
2025 Two homologous Zn2Cys6 transcription factors play crucial roles in host specificity of Colletotrichum orbiculare by controlling the expression of cucurbit-specific virulence effectors. The New phytologist 2 39888001
2024 Lysyl Oxidase Mediates Proliferation and Differentiation in the Esophageal Epithelium. Biomolecules 1 39766266
2010 Neuroprotective effects of active ingredients isolated from Pegasus laternarius on cultured cerebral neurons. Cellular and molecular neurobiology 1 20734129
2026 Gene variants in the pheromone vomeronasal receptors and QTLs around behavioral and fat metabolism genes associated with altered feed efficiency in cattle. Scientific reports 0 41639242
2026 NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy. Brain, behavior, and immunity 0 41713665
2026 Identification of Drug-resistant Cell Subpopulations in Colorectal Cancer Through Single-cell Analysis and Exploration of Potential Therapeutic Strategies. Current medicinal chemistry 0 42003098
2026 Multiomics Reveals IL-17 Drives Epithelial Keratinization and Proliferation via EHF in Odontogenic Keratocysts. International journal of molecular sciences 0 42123694
2024 Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids. bioRxiv : the preprint server for biology 0 38826379
2019 [Phenotypic and genotypic analysis of a girl carrying a 2q22.3 microduplication encompassing the MBD5 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 31055822

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