{"gene":"EZH2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2005,"finding":"EZH2, within the context of PRC2/3, directly interacts with DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and associates with DNMT activity in vivo. Binding of DNMTs to EZH2-repressed gene promoters depends on EZH2 presence, and EZH2 is required for DNA methylation at those promoters, functioning as a recruitment platform for DNMTs.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), bisulfite genomic sequencing","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, and bisulfite sequencing across multiple target genes; widely replicated finding","pmids":["16357870"],"is_preprint":false},{"year":1996,"finding":"Mouse EZH2 (Enx-1) encodes the murine homolog of Drosophila Enhancer of zeste and contains a conserved SET domain and a newly defined CXC domain. It is expressed ubiquitously in early embryogenesis and becomes restricted to nervous system and hematopoietic sites in later development.","method":"cDNA cloning, sequence analysis, in situ hybridization / Northern blot expression analysis","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cloning and expression profiling; domain architecture validated by sequence conservation across species, single lab","pmids":["8861097"],"is_preprint":false},{"year":2000,"finding":"ENX-1 (human EZH2) is required for proliferation of haematopoietic cells: it is upregulated upon T and B lymphocyte stimulation, downregulated upon granulocytic differentiation of HL-60 cells, and antisense knockdown suppresses DNA synthesis in HL-60 cells.","method":"Antisense oligodeoxynucleotide knockdown, flow cytometry, [3H]-thymidine incorporation (DNA synthesis assay)","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with specific proliferation phenotype, single lab, single method","pmids":["10792293"],"is_preprint":false},{"year":2014,"finding":"OGT-mediated O-GlcNAcylation of EZH2 at serine 75 stabilizes EZH2 protein and maintains PRC2 complex integrity. OGT knockdown specifically reduces EZH2 protein stability and H3K27me3 levels without affecting H3K27 demethylases. The EZH2 S75A mutant shows reduced stability.","method":"Co-immunoprecipitation, cosedimentation, site-directed mutagenesis (S75A), OGT knockdown, mass spectrometry, microarray, ChIP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of modification site, reciprocal Co-IP, functional rescue, multiple orthogonal methods in single rigorous study","pmids":["24474760"],"is_preprint":false},{"year":2020,"finding":"PRMT1 asymmetrically dimethylates EZH2 at R342, which inhibits CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating TRAF6-mediated ubiquitylation and proteasomal degradation of EZH2, resulting in EZH2 stabilization and promotion of breast cancer EMT and metastasis.","method":"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase/ubiquitylation assays, mass spectrometry, Western blot, invasion assays, xenograft models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical assays with mutagenesis, multiple orthogonal methods establishing PTM crosstalk mechanism","pmids":["32895488"],"is_preprint":false},{"year":2020,"finding":"EZH2 harbors a partially disordered transactivation domain (TAD) comprising the SRM and SANT1 regions. This TAD mediates protein oligomerization in a non-canonical PRC2 context and is sequestered in canonical PRC2. Cancer-specific phosphorylation events unlock the TAD, enabling interaction with the transcriptional coactivator p300 to activate gene expression.","method":"Crystal structure of EZH2-EED binary complex, NMR, mutagenesis, Co-immunoprecipitation, reporter gene assay, cell-based gene expression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical interaction assays and functional cell-based validation; multiple orthogonal methods","pmids":["32631994"],"is_preprint":false},{"year":2022,"finding":"EZH2 methylates non-histone substrate SMAD3 at K53 and K333. This methylation facilitates SMAD3 interaction with SARA (its membrane localization molecule), sustaining SMAD3 phosphorylation by the TGFβ receptor, thereby promoting SMAD3 activation, tumor metastasis, and poor survival outcomes in breast cancer.","method":"In vitro methylation assay, site-directed mutagenesis (K53/K333), Co-immunoprecipitation, TAT-peptide inhibition, xenograft models, patient sample analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of methylation, mutagenesis of substrate sites, Co-IP for complex, functional rescue with peptide inhibitor","pmids":["35085106"],"is_preprint":false},{"year":2022,"finding":"EZH2 methylates the pioneer factor FOXA1, contributing to activation of DNA damage repair (BER pathway) genes. EZH2 also interacts with transcriptional coactivator P300 via its transactivation domain to directly drive transcription of DDR genes in castration-resistant prostate cancer, independently of its canonical H3K27me3 repressive function.","method":"Gene expression profiling, ChIP-seq, CRISPR-Cas9 knockout screens, Co-immunoprecipitation, in vitro methylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including CRISPR screens, ChIP-seq, and in vitro assays; functional validation in cells and patient data","pmids":["35031563"],"is_preprint":false},{"year":2019,"finding":"EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma by directly increasing H3K27me3 levels on the promoters of both CD274 (encoding PD-L1) and IRF1 (an essential transcription factor for PD-L1 expression), without affecting IFNγ-STAT1 pathway activation.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, EZH2 knockdown, quantitative RT-PCR, Western blot, flow cytometry","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm direct promoter occupancy and functional repression; single lab","pmids":["31727135"],"is_preprint":false},{"year":2021,"finding":"EZH2 interacts with cMyc in a PRC2- and H3K27me3-independent manner in multiple myeloma cells, co-localizing with gene activation-associated marks to promote oncogenic transcription. This noncanonical EZH2-cMyc complex is distinct from the canonical EZH2-PRC2 repressive complex.","method":"Co-immunoprecipitation, ChIP-seq, EZH2 PROTAC degrader (MS177), RNA-seq, proliferation assays, xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP-seq demonstrating complex and genomic co-localization; functional validation with degrader; single lab","pmids":["36747009"],"is_preprint":false},{"year":2021,"finding":"PRMT5 physically interacts with EZH2, leading to enhanced EZH2 binding and H3K27me3 deposition at the CDKN2B (p15INK4b) promoter and epigenetic repression of CDKN2B to promote colorectal cancer progression.","method":"Co-immunoprecipitation, GST pulldown, ChIP assay, bisulfite sequencing, luciferase reporter assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown confirming physical interaction, ChIP confirming co-occupancy at target promoter; single lab","pmids":["33664859"],"is_preprint":false},{"year":2020,"finding":"USP7 deubiquitinates and stabilizes EZH2 protein. Overexpression of USP7 promotes EZH2 protein levels while a catalytically dead USP7 mutant does not; USP7 knockdown reduces EZH2 protein. USP7/EZH2 axis promotes cell growth, invasion and tumor formation.","method":"Co-immunoprecipitation, ubiquitination assay, USP7 knockdown/overexpression, site-directed mutagenesis of USP7 catalytic residue, in vivo xenograft","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and catalytic mutant validation; single lab","pmids":["32064169"],"is_preprint":false},{"year":2020,"finding":"EZH2-mediated H3K27me3 at the ACE2 promoter region represses ACE2 expression. Knockout of EZH2 in human embryonic stem cells results in significantly increased ACE2 expression, accompanied by decreased H3K27me3 and increased H3K27ac at the ACE2 promoter.","method":"EZH2 knockout, RNA-seq, ChIP-seq","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with ChIP-seq showing direct epigenetic mechanism at the target locus; single lab, single study","pmids":["32291076"],"is_preprint":false},{"year":2022,"finding":"EZH2 interacts with HP1BP3 in glioma stem cells, impairing H3K9 methylation, and EZH2-HP1BP3 co-activate WNT7B expression, thereby increasing temozolomide resistance and stemness of glioblastoma cells.","method":"Immunoprecipitation and mass spectrometry, co-immunoprecipitation, ChIP, RNA-seq, overexpression/knockdown, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS identifies interaction, co-IP confirms it, ChIP shows co-occupancy; single lab","pmids":["36517590"],"is_preprint":false},{"year":2022,"finding":"EZH2-mediated H3K27me3 promotes KRT14 transcription (rather than repression) in TNBC by attenuating binding of the transcriptional repressor SP1 to the KRT14 promoter, representing a non-canonical gene-activating function of H3K27me3/EZH2.","method":"ChIP assay, EZH2 knockdown, EZH2 inhibitor (EPZ6438), in vivo peritoneal metastasis model, SP1 binding assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter occupancy and SP1 displacement; functional validation in vivo; single lab","pmids":["36446780"],"is_preprint":false},{"year":2018,"finding":"EZH2 regulates NTRK1 (TrkA) expression via H3K27me3 modifications at the NTRK1 P1 promoter region in neuroblastoma, repressing NTRK1 transcript variants 1/2. EZH2 knockdown or inhibition induces NTRK1 expression and neuroblastoma cell differentiation; NTRK1 depletion cancels this differentiation.","method":"EZH2 lentiviral knockdown, ChIP assay, transcriptome microarray, bisulfite methylome analysis, EZH2 inhibitor treatment, neurite extension assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrative ChIP, methylome, and transcriptome; genetic rescue experiment; single lab","pmids":["29507419"],"is_preprint":false},{"year":2022,"finding":"Ezh2 promotes inflammasome activation in macrophages/microglia independently of its methyltransferase activity. Via its SANT2 domain, Ezh2 maintains H3K27 acetylation at the Neat1 lncRNA promoter, promoting chromatin accessibility and p65-mediated Neat1 transcription. p53 competes with Ezh2 at this promoter; loss of Ezh2 allows p53 to recruit SIRT1 for H3K27 deacetylation, suppressing Neat1 and inflammasome activation.","method":"ChIP, ATAC-seq, EZH2 knockdown/domain mutant, promoter-reporter assay, Co-immunoprecipitation, in vivo mouse models","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutant establishing methyltransferase-independent function, ChIP and ATAC-seq, competition assay; single lab","pmids":["35568718"],"is_preprint":false},{"year":2020,"finding":"SUMOylation of E2F1 enhances its binding to the EZH2 promoter, transcriptionally activating EZH2. Knockdown of the SUMO-activating enzyme SAE2 or pharmacologic SUMOylation inhibition reduces EZH2 mRNA, protein, and H3K27me3 levels.","method":"SAE2 knockdown, pharmacologic SUMOylation inhibition, ChIP, quantitative RT-PCR, Western blot, gene expression analysis across >6500 tumors","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates E2F1 promoter binding modulated by SUMO status, validated by genetic and pharmacologic intervention; single lab","pmids":["32816857"],"is_preprint":false}],"current_model":"EZH2 is the catalytic subunit of PRC2 that trimethylates histone H3 lysine 27 (H3K27me3) to silence gene transcription; it also recruits DNA methyltransferases to target promoters, methylates non-histone substrates (SMAD3, FOXA1), and acts as a transcriptional co-activator through a cryptic transactivation domain that interacts with p300 upon cancer-specific phosphorylation, with its own stability regulated by O-GlcNAcylation (OGT at S75), arginine methylation (PRMT1 at R342), and deubiquitination (USP7)."},"narrative":{"mechanistic_narrative":"EZH2 is a SET-domain histone methyltransferase that serves as the catalytic engine of Polycomb repressive complex 2 (PRC2), trimethylating histone H3 lysine 27 (H3K27me3) to silence target genes during development and in cancer [PMID:8861097, PMID:29507419]. Beyond depositing the repressive H3K27me3 mark, EZH2 functions as a recruitment platform that physically binds DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and is required for DNA methylation at its repressed promoters [PMID:16357870], coupling histone and DNA methylation to enforce stable gene silencing at loci including NTRK1, CD274/IRF1, ACE2, and CDKN2B [PMID:29507419, PMID:31727135, PMID:32291076, PMID:33664859]. EZH2 additionally methylates non-histone substrates: it dimethylates SMAD3 at K53/K333 to sustain TGFβ-receptor-driven SMAD3 activation and methylates the pioneer factor FOXA1, both promoting tumor progression [PMID:35085106, PMID:35031563]. A partially disordered transactivation domain (SRM/SANT1) sequestered in canonical PRC2 is unlocked by cancer-specific phosphorylation, allowing EZH2 to engage the coactivator p300 and directly activate transcription—for example of DNA-damage-repair genes in castration-resistant prostate cancer—independently of its H3K27me3 repressive activity [PMID:32631994, PMID:35031563]. This noncanonical, methyltransferase-independent activator role extends to PRC2-independent complexes with cMyc and HP1BP3 that drive oncogenic transcription, and to a SANT2-dependent maintenance of H3K27 acetylation at the Neat1 promoter promoting inflammasome activation [PMID:36747009, PMID:36517590, PMID:35568718]. EZH2 abundance is tightly controlled by post-translational modification: OGT-mediated O-GlcNAcylation at S75 stabilizes the protein and maintains PRC2 integrity [PMID:24474760], PRMT1-mediated dimethylation at R342 blocks CDK1 phosphorylation and TRAF6-dependent degradation [PMID:32895488], and USP7 deubiquitinates and stabilizes EZH2 [PMID:32064169].","teleology":[{"year":1996,"claim":"Establishing the mammalian ortholog of Drosophila Enhancer of zeste defined EZH2's conserved SET and CXC domain architecture and its developmentally regulated expression, framing it as a candidate epigenetic regulator.","evidence":"cDNA cloning, sequence analysis, and in situ/Northern expression profiling of mouse Enx-1","pmids":["8861097"],"confidence":"Medium","gaps":["No enzymatic activity demonstrated","Substrate and complex membership unknown at this stage"]},{"year":2000,"claim":"Linking EZH2 expression to hematopoietic proliferation showed it is functionally required for cell division, motivating its study as a proliferation-promoting factor.","evidence":"Antisense knockdown and DNA synthesis assays in stimulated lymphocytes and HL-60 cells","pmids":["10792293"],"confidence":"Medium","gaps":["Molecular mechanism linking EZH2 to proliferation not defined","Single cell-line/single-method"]},{"year":2005,"claim":"Discovery that EZH2 physically recruits DNMTs to target promoters connected histone H3K27 methylation to DNA methylation, defining EZH2 as a hub coordinating two repressive epigenetic layers.","evidence":"Reciprocal Co-IP, ChIP, and bisulfite sequencing across multiple target genes","pmids":["16357870"],"confidence":"High","gaps":["Stoichiometry and direct vs indirect DNMT contact not fully resolved","Generality across genomic context unaddressed"]},{"year":2014,"claim":"Identifying O-GlcNAcylation at S75 revealed that EZH2 protein stability and PRC2 integrity are controlled post-translationally, establishing a nutrient-sensing input to H3K27me3 levels.","evidence":"S75A mutagenesis, OGT knockdown, Co-IP, cosedimentation, mass spectrometry, ChIP","pmids":["24474760"],"confidence":"High","gaps":["Upstream signals controlling OGT targeting of EZH2 unknown","Effect on non-canonical EZH2 functions untested"]},{"year":2018,"claim":"Demonstrating EZH2-driven H3K27me3 repression of NTRK1 in neuroblastoma tied EZH2 to a differentiation-blocking program, with genetic rescue confirming NTRK1 as the functional effector.","evidence":"EZH2 knockdown/inhibitor, ChIP, methylome and transcriptome profiling, neurite extension and NTRK1-depletion rescue","pmids":["29507419"],"confidence":"Medium","gaps":["Direct vs PRC2-dependent recruitment to NTRK1 not dissected","Single lineage context"]},{"year":2019,"claim":"Showing EZH2 represses PD-L1 and IRF1 via H3K27me3 connected its silencing activity to immune evasion regulation independently of IFNγ-STAT1 signaling.","evidence":"ChIP, dual-luciferase reporter, knockdown, qRT-PCR, flow cytometry in hepatocellular carcinoma","pmids":["31727135"],"confidence":"Medium","gaps":["Single tumor type","Reciprocal validation of recruitment limited"]},{"year":2020,"claim":"Structural and biochemical work defined a cryptic transactivation domain that, when unlocked by cancer-specific phosphorylation, recruits p300 — establishing a PRC2-independent transcriptional activator role for EZH2.","evidence":"EZH2-EED crystal structure, NMR, mutagenesis, Co-IP, reporter and cell-based gene expression assays","pmids":["32631994"],"confidence":"High","gaps":["Identity of the specific cancer kinases in vivo not fully mapped","Genome-wide activation targets undefined in this study"]},{"year":2020,"claim":"Defining the PRMT1–CDK1–TRAF6 PTM-crosstalk axis and USP7-mediated deubiquitination clarified how EZH2 protein levels are stabilized to promote metastasis and tumor growth.","evidence":"In vitro kinase/ubiquitylation assays, site-directed mutagenesis, Co-IP, USP7 catalytic-dead mutant, xenografts","pmids":["32895488","32064169"],"confidence":"High","gaps":["Interplay between R342 methylation, USP7, and O-GlcNAcylation not integrated","Tissue-specificity of these inputs unclear"]},{"year":2020,"claim":"Mapping E2F1-SUMOylation as a transcriptional activator of the EZH2 promoter and EZH2-driven H3K27me3 repression of ACE2 expanded the regulatory loops governing EZH2 expression and its target repertoire.","evidence":"SAE2 knockdown/SUMO inhibition with ChIP (E2F1) and EZH2 knockout with RNA-seq/ChIP-seq (ACE2)","pmids":["32816857","32291076"],"confidence":"Medium","gaps":["Physiological contexts of ACE2 regulation beyond stem cells untested","SUMO-EZH2 transcriptional loop generality unknown"]},{"year":2022,"claim":"A series of studies established EZH2's non-histone methylation (SMAD3, FOXA1) and PRC2-independent activating complexes (cMyc, HP1BP3, SANT2-dependent Neat1 control), reframing EZH2 as a context-dependent activator as well as a repressor.","evidence":"In vitro methylation assays, site mutagenesis, Co-IP/IP-MS, ChIP-seq, ATAC-seq, domain mutants, peptide inhibitors, xenografts","pmids":["35085106","35031563","36747009","36517590","35568718","36446780"],"confidence":"Medium","gaps":["Switch determinants between repressive and activating modes not unified","Most activating functions shown in single lineages","Structural basis of cMyc/HP1BP3 complexes undefined"]},{"year":null,"claim":"How EZH2's distinct PTMs and binding partners are integrated to toggle between PRC2-dependent repression and PRC2-independent transcriptional activation in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phosphorylation/methylation status to repressor-vs-activator output","Endogenous prevalence of non-canonical complexes relative to canonical PRC2 not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,3,6,7,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,7]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7,9,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,15]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,7,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,11]}],"complexes":["PRC2"],"partners":["DNMT1","DNMT3A","DNMT3B","OGT","USP7","PRMT1","EED","EP300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15910","full_name":"Histone-lysine N-methyltransferase EZH2","aliases":["ENX-1","Enhancer of zeste homolog 2","Lysine N-methyltransferase 6"],"length_aa":746,"mass_kda":85.4,"function":"Catalytic subunit of the PRC2/EED-EZH2 complex, a Polycomb group (PcG) complex that methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene (PubMed:14532106, PubMed:15225548, PubMed:15385962, PubMed:16618801, PubMed:16936726, PubMed:17344414, PubMed:22323599, PubMed:24474760, PubMed:26581166, PubMed:30026490, PubMed:30923826). Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively (PubMed:15231737, PubMed:17210787, PubMed:18285464, PubMed:22323599, PubMed:30923826). Displays a preference for substrates with less methylation, loses activity when progressively more methyl groups are incorporated into H3K27, H3K27me0 > H3K27me1 > H3K27me2 (PubMed:22323599, PubMed:30923826). Compared to EZH1-containing complexes, it is more abundant in embryonic stem cells and plays a major role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation (PubMed:19026781). The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems (PubMed:16357870, PubMed:17200670). Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1, CDKN2A and retinoic acid target genes (PubMed:16179254, PubMed:18086877, PubMed:20935635). EZH2 can also methylate non-histone proteins such as the transcription factor GATA4 and the nuclear receptor RORA (PubMed:23063525). Regulates the circadian clock via histone methylation at the promoter of the circadian genes (PubMed:16717091). Essential for the CRY1/2-mediated repression of the transcriptional activation of PER1/2 by the CLOCK-BMAL1 heterodimer; involved in the di and trimethylation of 'Lys-27' of histone H3 on PER1/2 promoters which is necessary for the CRY1/2 proteins to inhibit transcription (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q15910/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EZH2","classification":"Not Classified","n_dependent_lines":97,"n_total_lines":1208,"dependency_fraction":0.0802980132450331},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"H1F0","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EZH2","total_profiled":1310},"omim":[{"mim_id":"621547","title":"ZDHHC PALMITOYLTRANSFERASE 4; ZDHHC4","url":"https://www.omim.org/entry/621547"},{"mim_id":"621305","title":"CARDIAC MESODERM ENHANCER-ASSOCIATED NONCODING RNA; CARMN","url":"https://www.omim.org/entry/621305"},{"mim_id":"620942","title":"SYNPO2 INTRON SENSE-OVERLAPPING LONG NONCODING RNA","url":"https://www.omim.org/entry/620942"},{"mim_id":"620377","title":"ARMADILLO REPEAT-CONTAINING PROTEIN 12; ARMC12","url":"https://www.omim.org/entry/620377"},{"mim_id":"619041","title":"MONOSOMY 7 MYELODYSPLASIA AND LEUKEMIA SYNDROME 2; M7MLS2","url":"https://www.omim.org/entry/619041"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":23.9},{"tissue":"lymphoid tissue","ntpm":34.1},{"tissue":"testis","ntpm":24.5}],"url":"https://www.proteinatlas.org/search/EZH2"},"hgnc":{"alias_symbol":["EZH1","ENX-1","KMT6","KMT6A"],"prev_symbol":[]},"alphafold":{"accession":"Q15910","domains":[{"cath_id":"-","chopping":"10-50_162-176_219-255","consensus_level":"medium","plddt":85.4635,"start":10,"end":255},{"cath_id":"-","chopping":"263-338_431-476","consensus_level":"medium","plddt":85.4001,"start":263,"end":476},{"cath_id":"-","chopping":"557-604","consensus_level":"medium","plddt":93.8083,"start":557,"end":604},{"cath_id":"2.170.270.10","chopping":"613-726","consensus_level":"medium","plddt":94.2638,"start":613,"end":726}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15910","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15910-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15910-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EZH2","jax_strain_url":"https://www.jax.org/strain/search?query=EZH2"},"sequence":{"accession":"Q15910","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15910.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15910/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15910"}},"corpus_meta":[{"pmid":"16357870","id":"PMC_16357870","title":"The 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Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35856444","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46723,"output_tokens":4499,"usd":0.103827,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12414,"output_tokens":3847,"usd":0.079122,"stage2_stop_reason":"end_turn"},"total_usd":0.182949,"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\": 2005,\n      \"finding\": \"EZH2, within the context of PRC2/3, directly interacts with DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and associates with DNMT activity in vivo. Binding of DNMTs to EZH2-repressed gene promoters depends on EZH2 presence, and EZH2 is required for DNA methylation at those promoters, functioning as a recruitment platform for DNMTs.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), bisulfite genomic sequencing\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, and bisulfite sequencing across multiple target genes; widely replicated finding\",\n      \"pmids\": [\"16357870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mouse EZH2 (Enx-1) encodes the murine homolog of Drosophila Enhancer of zeste and contains a conserved SET domain and a newly defined CXC domain. It is expressed ubiquitously in early embryogenesis and becomes restricted to nervous system and hematopoietic sites in later development.\",\n      \"method\": \"cDNA cloning, sequence analysis, in situ hybridization / Northern blot expression analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cloning and expression profiling; domain architecture validated by sequence conservation across species, single lab\",\n      \"pmids\": [\"8861097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ENX-1 (human EZH2) is required for proliferation of haematopoietic cells: it is upregulated upon T and B lymphocyte stimulation, downregulated upon granulocytic differentiation of HL-60 cells, and antisense knockdown suppresses DNA synthesis in HL-60 cells.\",\n      \"method\": \"Antisense oligodeoxynucleotide knockdown, flow cytometry, [3H]-thymidine incorporation (DNA synthesis assay)\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with specific proliferation phenotype, single lab, single method\",\n      \"pmids\": [\"10792293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OGT-mediated O-GlcNAcylation of EZH2 at serine 75 stabilizes EZH2 protein and maintains PRC2 complex integrity. OGT knockdown specifically reduces EZH2 protein stability and H3K27me3 levels without affecting H3K27 demethylases. The EZH2 S75A mutant shows reduced stability.\",\n      \"method\": \"Co-immunoprecipitation, cosedimentation, site-directed mutagenesis (S75A), OGT knockdown, mass spectrometry, microarray, ChIP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of modification site, reciprocal Co-IP, functional rescue, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"24474760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PRMT1 asymmetrically dimethylates EZH2 at R342, which inhibits CDK1-mediated phosphorylation of EZH2 at T345 and T487, thereby attenuating TRAF6-mediated ubiquitylation and proteasomal degradation of EZH2, resulting in EZH2 stabilization and promotion of breast cancer EMT and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, in vitro kinase/ubiquitylation assays, mass spectrometry, Western blot, invasion assays, xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical assays with mutagenesis, multiple orthogonal methods establishing PTM crosstalk mechanism\",\n      \"pmids\": [\"32895488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EZH2 harbors a partially disordered transactivation domain (TAD) comprising the SRM and SANT1 regions. This TAD mediates protein oligomerization in a non-canonical PRC2 context and is sequestered in canonical PRC2. Cancer-specific phosphorylation events unlock the TAD, enabling interaction with the transcriptional coactivator p300 to activate gene expression.\",\n      \"method\": \"Crystal structure of EZH2-EED binary complex, NMR, mutagenesis, Co-immunoprecipitation, reporter gene assay, cell-based gene expression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical interaction assays and functional cell-based validation; multiple orthogonal methods\",\n      \"pmids\": [\"32631994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 methylates non-histone substrate SMAD3 at K53 and K333. This methylation facilitates SMAD3 interaction with SARA (its membrane localization molecule), sustaining SMAD3 phosphorylation by the TGFβ receptor, thereby promoting SMAD3 activation, tumor metastasis, and poor survival outcomes in breast cancer.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis (K53/K333), Co-immunoprecipitation, TAT-peptide inhibition, xenograft models, patient sample analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of methylation, mutagenesis of substrate sites, Co-IP for complex, functional rescue with peptide inhibitor\",\n      \"pmids\": [\"35085106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 methylates the pioneer factor FOXA1, contributing to activation of DNA damage repair (BER pathway) genes. EZH2 also interacts with transcriptional coactivator P300 via its transactivation domain to directly drive transcription of DDR genes in castration-resistant prostate cancer, independently of its canonical H3K27me3 repressive function.\",\n      \"method\": \"Gene expression profiling, ChIP-seq, CRISPR-Cas9 knockout screens, Co-immunoprecipitation, in vitro methylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including CRISPR screens, ChIP-seq, and in vitro assays; functional validation in cells and patient data\",\n      \"pmids\": [\"35031563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma by directly increasing H3K27me3 levels on the promoters of both CD274 (encoding PD-L1) and IRF1 (an essential transcription factor for PD-L1 expression), without affecting IFNγ-STAT1 pathway activation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, EZH2 knockdown, quantitative RT-PCR, Western blot, flow cytometry\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm direct promoter occupancy and functional repression; single lab\",\n      \"pmids\": [\"31727135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EZH2 interacts with cMyc in a PRC2- and H3K27me3-independent manner in multiple myeloma cells, co-localizing with gene activation-associated marks to promote oncogenic transcription. This noncanonical EZH2-cMyc complex is distinct from the canonical EZH2-PRC2 repressive complex.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, EZH2 PROTAC degrader (MS177), RNA-seq, proliferation assays, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP-seq demonstrating complex and genomic co-localization; functional validation with degrader; single lab\",\n      \"pmids\": [\"36747009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 physically interacts with EZH2, leading to enhanced EZH2 binding and H3K27me3 deposition at the CDKN2B (p15INK4b) promoter and epigenetic repression of CDKN2B to promote colorectal cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, ChIP assay, bisulfite sequencing, luciferase reporter assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and GST pulldown confirming physical interaction, ChIP confirming co-occupancy at target promoter; single lab\",\n      \"pmids\": [\"33664859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP7 deubiquitinates and stabilizes EZH2 protein. Overexpression of USP7 promotes EZH2 protein levels while a catalytically dead USP7 mutant does not; USP7 knockdown reduces EZH2 protein. USP7/EZH2 axis promotes cell growth, invasion and tumor formation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, USP7 knockdown/overexpression, site-directed mutagenesis of USP7 catalytic residue, in vivo xenograft\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and catalytic mutant validation; single lab\",\n      \"pmids\": [\"32064169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EZH2-mediated H3K27me3 at the ACE2 promoter region represses ACE2 expression. Knockout of EZH2 in human embryonic stem cells results in significantly increased ACE2 expression, accompanied by decreased H3K27me3 and increased H3K27ac at the ACE2 promoter.\",\n      \"method\": \"EZH2 knockout, RNA-seq, ChIP-seq\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with ChIP-seq showing direct epigenetic mechanism at the target locus; single lab, single study\",\n      \"pmids\": [\"32291076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2 interacts with HP1BP3 in glioma stem cells, impairing H3K9 methylation, and EZH2-HP1BP3 co-activate WNT7B expression, thereby increasing temozolomide resistance and stemness of glioblastoma cells.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry, co-immunoprecipitation, ChIP, RNA-seq, overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS identifies interaction, co-IP confirms it, ChIP shows co-occupancy; single lab\",\n      \"pmids\": [\"36517590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EZH2-mediated H3K27me3 promotes KRT14 transcription (rather than repression) in TNBC by attenuating binding of the transcriptional repressor SP1 to the KRT14 promoter, representing a non-canonical gene-activating function of H3K27me3/EZH2.\",\n      \"method\": \"ChIP assay, EZH2 knockdown, EZH2 inhibitor (EPZ6438), in vivo peritoneal metastasis model, SP1 binding assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter occupancy and SP1 displacement; functional validation in vivo; single lab\",\n      \"pmids\": [\"36446780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EZH2 regulates NTRK1 (TrkA) expression via H3K27me3 modifications at the NTRK1 P1 promoter region in neuroblastoma, repressing NTRK1 transcript variants 1/2. EZH2 knockdown or inhibition induces NTRK1 expression and neuroblastoma cell differentiation; NTRK1 depletion cancels this differentiation.\",\n      \"method\": \"EZH2 lentiviral knockdown, ChIP assay, transcriptome microarray, bisulfite methylome analysis, EZH2 inhibitor treatment, neurite extension assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrative ChIP, methylome, and transcriptome; genetic rescue experiment; single lab\",\n      \"pmids\": [\"29507419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ezh2 promotes inflammasome activation in macrophages/microglia independently of its methyltransferase activity. Via its SANT2 domain, Ezh2 maintains H3K27 acetylation at the Neat1 lncRNA promoter, promoting chromatin accessibility and p65-mediated Neat1 transcription. p53 competes with Ezh2 at this promoter; loss of Ezh2 allows p53 to recruit SIRT1 for H3K27 deacetylation, suppressing Neat1 and inflammasome activation.\",\n      \"method\": \"ChIP, ATAC-seq, EZH2 knockdown/domain mutant, promoter-reporter assay, Co-immunoprecipitation, in vivo mouse models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutant establishing methyltransferase-independent function, ChIP and ATAC-seq, competition assay; single lab\",\n      \"pmids\": [\"35568718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SUMOylation of E2F1 enhances its binding to the EZH2 promoter, transcriptionally activating EZH2. Knockdown of the SUMO-activating enzyme SAE2 or pharmacologic SUMOylation inhibition reduces EZH2 mRNA, protein, and H3K27me3 levels.\",\n      \"method\": \"SAE2 knockdown, pharmacologic SUMOylation inhibition, ChIP, quantitative RT-PCR, Western blot, gene expression analysis across >6500 tumors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates E2F1 promoter binding modulated by SUMO status, validated by genetic and pharmacologic intervention; single lab\",\n      \"pmids\": [\"32816857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EZH2 is the catalytic subunit of PRC2 that trimethylates histone H3 lysine 27 (H3K27me3) to silence gene transcription; it also recruits DNA methyltransferases to target promoters, methylates non-histone substrates (SMAD3, FOXA1), and acts as a transcriptional co-activator through a cryptic transactivation domain that interacts with p300 upon cancer-specific phosphorylation, with its own stability regulated by O-GlcNAcylation (OGT at S75), arginine methylation (PRMT1 at R342), and deubiquitination (USP7).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EZH2 is a SET-domain histone methyltransferase that serves as the catalytic engine of Polycomb repressive complex 2 (PRC2), trimethylating histone H3 lysine 27 (H3K27me3) to silence target genes during development and in cancer [#1, #15]. Beyond depositing the repressive H3K27me3 mark, EZH2 functions as a recruitment platform that physically binds DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and is required for DNA methylation at its repressed promoters [#0], coupling histone and DNA methylation to enforce stable gene silencing at loci including NTRK1, CD274/IRF1, ACE2, and CDKN2B [#15, #8, #12, #10]. EZH2 additionally methylates non-histone substrates: it dimethylates SMAD3 at K53/K333 to sustain TGFβ-receptor-driven SMAD3 activation and methylates the pioneer factor FOXA1, both promoting tumor progression [#6, #7]. A partially disordered transactivation domain (SRM/SANT1) sequestered in canonical PRC2 is unlocked by cancer-specific phosphorylation, allowing EZH2 to engage the coactivator p300 and directly activate transcription—for example of DNA-damage-repair genes in castration-resistant prostate cancer—independently of its H3K27me3 repressive activity [#5, #7]. This noncanonical, methyltransferase-independent activator role extends to PRC2-independent complexes with cMyc and HP1BP3 that drive oncogenic transcription, and to a SANT2-dependent maintenance of H3K27 acetylation at the Neat1 promoter promoting inflammasome activation [#9, #13, #16]. EZH2 abundance is tightly controlled by post-translational modification: OGT-mediated O-GlcNAcylation at S75 stabilizes the protein and maintains PRC2 integrity [#3], PRMT1-mediated dimethylation at R342 blocks CDK1 phosphorylation and TRAF6-dependent degradation [#4], and USP7 deubiquitinates and stabilizes EZH2 [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the mammalian ortholog of Drosophila Enhancer of zeste defined EZH2's conserved SET and CXC domain architecture and its developmentally regulated expression, framing it as a candidate epigenetic regulator.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and in situ/Northern expression profiling of mouse Enx-1\",\n      \"pmids\": [\"8861097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"Substrate and complex membership unknown at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linking EZH2 expression to hematopoietic proliferation showed it is functionally required for cell division, motivating its study as a proliferation-promoting factor.\",\n      \"evidence\": \"Antisense knockdown and DNA synthesis assays in stimulated lymphocytes and HL-60 cells\",\n      \"pmids\": [\"10792293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking EZH2 to proliferation not defined\", \"Single cell-line/single-method\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that EZH2 physically recruits DNMTs to target promoters connected histone H3K27 methylation to DNA methylation, defining EZH2 as a hub coordinating two repressive epigenetic layers.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, and bisulfite sequencing across multiple target genes\",\n      \"pmids\": [\"16357870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct vs indirect DNMT contact not fully resolved\", \"Generality across genomic context unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying O-GlcNAcylation at S75 revealed that EZH2 protein stability and PRC2 integrity are controlled post-translationally, establishing a nutrient-sensing input to H3K27me3 levels.\",\n      \"evidence\": \"S75A mutagenesis, OGT knockdown, Co-IP, cosedimentation, mass spectrometry, ChIP\",\n      \"pmids\": [\"24474760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling OGT targeting of EZH2 unknown\", \"Effect on non-canonical EZH2 functions untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating EZH2-driven H3K27me3 repression of NTRK1 in neuroblastoma tied EZH2 to a differentiation-blocking program, with genetic rescue confirming NTRK1 as the functional effector.\",\n      \"evidence\": \"EZH2 knockdown/inhibitor, ChIP, methylome and transcriptome profiling, neurite extension and NTRK1-depletion rescue\",\n      \"pmids\": [\"29507419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs PRC2-dependent recruitment to NTRK1 not dissected\", \"Single lineage context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing EZH2 represses PD-L1 and IRF1 via H3K27me3 connected its silencing activity to immune evasion regulation independently of IFNγ-STAT1 signaling.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, knockdown, qRT-PCR, flow cytometry in hepatocellular carcinoma\",\n      \"pmids\": [\"31727135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor type\", \"Reciprocal validation of recruitment limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structural and biochemical work defined a cryptic transactivation domain that, when unlocked by cancer-specific phosphorylation, recruits p300 — establishing a PRC2-independent transcriptional activator role for EZH2.\",\n      \"evidence\": \"EZH2-EED crystal structure, NMR, mutagenesis, Co-IP, reporter and cell-based gene expression assays\",\n      \"pmids\": [\"32631994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific cancer kinases in vivo not fully mapped\", \"Genome-wide activation targets undefined in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining the PRMT1–CDK1–TRAF6 PTM-crosstalk axis and USP7-mediated deubiquitination clarified how EZH2 protein levels are stabilized to promote metastasis and tumor growth.\",\n      \"evidence\": \"In vitro kinase/ubiquitylation assays, site-directed mutagenesis, Co-IP, USP7 catalytic-dead mutant, xenografts\",\n      \"pmids\": [\"32895488\", \"32064169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between R342 methylation, USP7, and O-GlcNAcylation not integrated\", \"Tissue-specificity of these inputs unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping E2F1-SUMOylation as a transcriptional activator of the EZH2 promoter and EZH2-driven H3K27me3 repression of ACE2 expanded the regulatory loops governing EZH2 expression and its target repertoire.\",\n      \"evidence\": \"SAE2 knockdown/SUMO inhibition with ChIP (E2F1) and EZH2 knockout with RNA-seq/ChIP-seq (ACE2)\",\n      \"pmids\": [\"32816857\", \"32291076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts of ACE2 regulation beyond stem cells untested\", \"SUMO-EZH2 transcriptional loop generality unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A series of studies established EZH2's non-histone methylation (SMAD3, FOXA1) and PRC2-independent activating complexes (cMyc, HP1BP3, SANT2-dependent Neat1 control), reframing EZH2 as a context-dependent activator as well as a repressor.\",\n      \"evidence\": \"In vitro methylation assays, site mutagenesis, Co-IP/IP-MS, ChIP-seq, ATAC-seq, domain mutants, peptide inhibitors, xenografts\",\n      \"pmids\": [\"35085106\", \"35031563\", \"36747009\", \"36517590\", \"35568718\", \"36446780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Switch determinants between repressive and activating modes not unified\", \"Most activating functions shown in single lineages\", \"Structural basis of cMyc/HP1BP3 complexes undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EZH2's distinct PTMs and binding partners are integrated to toggle between PRC2-dependent repression and PRC2-independent transcriptional activation in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phosphorylation/methylation status to repressor-vs-activator output\", \"Endogenous prevalence of non-canonical complexes relative to canonical PRC2 not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 3, 6, 7, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 7, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 11]}\n    ],\n    \"complexes\": [\"PRC2\"],\n    \"partners\": [\"DNMT1\", \"DNMT3A\", \"DNMT3B\", \"OGT\", \"USP7\", \"PRMT1\", \"EED\", \"EP300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}