Affinage

EZH1

Histone-lysine N-methyltransferase EZH1 · UniProt Q92800

Length
747 aa
Mass
85.3 kDa
Annotated
2026-06-09
88 papers in source corpus 33 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EZH1 is the catalytic subunit of a noncanonical PRC2 complex that methylates histone H3K27 in vitro and in vivo, preferentially preserving H3K27me3 at developmental regulator genes in slowly proliferating and post-mitotic cells where it compensates for EZH2 (PMID:19026780, PMID:19026781). Compared with EZH2, PRC2-EZH1 is a weak di-/trimethyltransferase but uniquely represses chromatinized templates and compacts chromatin in a SAM-independent manner, a property that depends on PRC2-EZH1 dimerization on the nucleosome and on a divergent EZH1/2 loop required for both nucleosome binding and catalysis (PMID:19026781, PMID:33514705). EZH1 and EZH2 act primarily within canonical PRC2, and their compensatory relationship is proliferation-dependent: EZH1 substitutes for EZH2 in slowly dividing cells but not rapidly dividing ones, and its loss requires SUZ12 for complex integrity (PMID:30867289). EZH1-specific H3K27 monomethylation is maintained at Polycomb regions even when EZH2-selective inhibitors deplete H3K27me2/3, so that only dual EZH1/2 inhibition erases all H3K27 methylation states (PMID:41000734). Beyond canonical chromatin repression, EZH1 also methylates the non-histone substrate AML1-ETO at Lys43 through its SET domain, augmenting AML1-ETO-dependent transcriptional repression (PMID:31699991), and acts through methylation-independent mechanisms to promote RNA Pol II elongation at active genes (PMID:22196887) and to maintain Notch pathway expression that enforces muscle stem cell quiescence (PMID:37105173). EZH1 functions are developmentally pivotal: it is required for skeletal muscle differentiation through EZH2-to-EZH1 PRC2 exchange at myogenic loci (PMID:21892963), maintains adult hematopoietic stem cells upstream of Cdkn2a (PMID:23122289) while repressing precocious haematopoietic multipotency in the embryo (PMID:29342143), and is necessary and sufficient for neural progenitor differentiation (PMID:37433783). Recurrent gain-of-function mutations drive disease: the Q571R substitution enhances EZH1 methyltransferase and chromatin-compaction activity in thyroid cancer (PMID:27500488), and dominant missense variants increasing methyltransferase activity, along with recessive loss-of-function alleles, cause neurodevelopmental disorders (PMID:37433783).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2008 High

    Established that EZH1, like EZH2, is a bona fide H3K27 methyltransferase within a distinct PRC2 complex and is the source of residual H3K27 methylation in EZH2-null cells, defining a compensatory branch of Polycomb silencing.

    Evidence In vitro methyltransferase assays, Co-IP, ChIP and genetic knockdown/knockout in ESCs, replicated by a companion study showing weak di-/trimethylation but robust SAM-independent chromatin compaction by EM

    PMID:19026780 PMID:19026781

    Open questions at the time
    • Structural basis of weak methyltransferase activity versus strong compaction not resolved at this stage
    • In vivo balance between EZH1 and EZH2 across tissues not mapped
  2. 2011 High

    Showed EZH1 has activities beyond gene repression — it associates with active marks and RNA Pol II and promotes Pol II elongation — and that EZH2-to-EZH1 PRC2 exchange at myogenic loci is required for muscle differentiation.

    Evidence Genome-wide ChIP-seq, Pol II ChIP, knockdown/overexpression rescue in differentiating muscle cells, and ChIP-based occupancy analysis with Msk1/H3S28ph regulation

    PMID:21892963 PMID:22196887

    Open questions at the time
    • Mechanism by which EZH1 promotes elongation independent of H3K27 methylation unresolved
    • Direct demonstration that elongation function is separable from PRC2 catalysis lacking
  3. 2012 High

    Defined an in vivo physiological role: EZH1-PRC2 H3K27 mono/dimethylation maintains adult HSC self-renewal by repressing Cdkn2a, preventing senescence.

    Evidence Conditional knockout mice, H3K27me1/2/3 ChIP-seq, transplantation, and Ezh1/Cdkn2a double-KO epistasis rescue

    PMID:23122289

    Open questions at the time
    • Whether the same Cdkn2a axis governs EZH1 function in non-hematopoietic tissues unknown
    • Contribution of H3K27me1/2 versus me3 to repression not dissected
  4. 2013 High

    Provided pharmacological access by characterizing a SAM-competitive inhibitor active against both EZH1 and EZH2, enabling cellular interrogation of H3K27me3.

    Evidence In vitro enzyme inhibition with defined competition mode and cell-based H3K27me3 measurement

    PMID:23614352

    Open questions at the time
    • No EZH1-selective compound established here
    • Cellular selectivity over EZH2 not achieved
  5. 2016 Medium

    Revealed methylation-dependent and methylation-independent gene-activating roles for EZH1 in inflammatory signaling, expanding its functional repertoire beyond repression.

    Evidence ChIP and SET-domain mutant rescue at the Tollip promoter in dendritic cells/macrophages, and reciprocal Co-IP plus ChIP-seq with UXT/SUZ12 at NF-kB target genes without H3K27me change

    PMID:25687760 PMID:27127229

    Open questions at the time
    • How EZH1 switches between repressive and activating modes at different loci unknown
    • UXT-EZH1-SUZ12 complex stoichiometry and architecture undefined
  6. 2016 Medium

    Identified EZH1 as a cancer driver via the recurrent Q571R gain-of-function mutation that increases H3K27 trimethylation and proliferation, often co-occurring with TSHR/GNAS mutations.

    Evidence Whole-exome and targeted sequencing of thyroid adenomas with cell-based H3K27me3 and proliferation assays expressing EZH1-Q571R

    PMID:27500488

    Open questions at the time
    • Biochemical basis of Q571R hyperactivity not resolved at this stage
    • Causal sequence of EZH1 versus TSHR/GNAS hits unproven
  7. 2017 Medium

    Demonstrated EZH1's non-histone methyltransferase capacity and additional tissue-specific and stress-sensing functions, including a cytoplasmic SET-lacking isoform controlling nuclear PRC2-EZH1 assembly.

    Evidence Isoform cloning and fractionation for Ezh1beta cytoplasmic localization and EED/SUZ12 assembly control, cardiac-specific rescue ChIP-seq, and ccRCC loss-of-function dependency screens

    PMID:28346433 PMID:28512107 PMID:28701475

    Open questions at the time
    • Signal transduced by cytoplasmic Ezh1beta to nuclear PRC2 not defined
    • Generality of EZH1 dependency across tumor types beyond ccRCC unclear
  8. 2018 High

    Showed EZH1 restrains developmental haematopoietic multipotency, opposite to its adult HSC-maintaining role, establishing context-dependent control of stem cell fate.

    Evidence shRNA knockdown in human iPSC differentiation and Ezh1 germline-knockout mouse with in vivo definitive HSC functional assays

    PMID:29342143

    Open questions at the time
    • Target genes mediating embryonic multipotency repression not identified
    • Reconciliation of embryonic repressive versus adult maintaining roles mechanistically open
  9. 2019 High

    Defined EZH1 as a direct methyltransferase of the AML1-ETO oncofusion at Lys43 via WD-domain binding, linking EZH1 catalysis to leukemic transcriptional repression of tumor suppressors.

    Evidence Co-IP domain mapping, in vitro methylation assay, point mutation/domain deletion, reporter assays and xenografts

    PMID:31699991

    Open questions at the time
    • Other non-histone substrates of EZH1 not surveyed
    • Whether AML1-ETO methylation occurs within intact PRC2 unresolved
  10. 2019 Medium

    Consolidated that EZH1/2 act primarily within canonical PRC2 with proliferation-dependent redundancy and clarified genome-wide reciprocal redistribution between the two enzymes in lymphoma.

    Evidence Conditional KO, pharmacological inhibition, Co-IP for complex integrity, and genome-wide ChIP-seq comparing EZH1/2 occupancy

    PMID:30867289 PMID:31747604

    Open questions at the time
    • Quantitative determinants of when EZH1 can substitute for EZH2 not defined
    • Mechanism of mutual interference between co-expressed enzymes unclear
  11. 2021 High

    Provided structural mechanism for EZH1's distinctive chromatin compaction by showing nucleosome-bound PRC2:EZH1 dimers and a divergent loop essential for both binding and catalysis, and linked stress-responsive PRC2-EZH1 to lncRNA Malat-1.

    Evidence Cryo-EM of monomer and nucleosome-bound dimer with mutagenesis and in vitro assays, plus Co-IP and Malat-1 knockdown with ChIP in oxidative-stressed myotubes

    PMID:33514705 PMID:34531374

    Open questions at the time
    • Physiological prevalence of dimeric versus monomeric PRC2:EZH1 in cells unknown
    • How Malat-1 controls EED nuclear shuttling mechanistically undefined
  12. 2023 High

    Established a methylation-independent in vivo function: EZH1 sustains Notch pathway expression to maintain muscle stem cell quiescence, decoupling an EZH1 phenotype from H3K27 methylation.

    Evidence Genetic knockout, transcriptomics, ChIP excluding H3K27me dependence, and Notch transgene rescue of MuSC quiescence

    PMID:37105173

    Open questions at the time
    • How EZH1 activates Notch genes without H3K27me deposition unresolved
    • Whether this mechanism extends to other quiescent stem cell populations untested
  13. 2023 High

    Connected EZH1 variants to human neurodevelopmental disease with bidirectional mechanism — recessive loss-of-function and dominant gain-of-function — and validated EZH1's necessity and sufficiency for neural differentiation.

    Evidence Patient-variant biochemistry, in vitro methyltransferase assays, chick neural tube electroporation, iPSC organoids, and transgenic Drosophila for the A678G gain-of-function allele

    PMID:37314226 PMID:37433783

    Open questions at the time
    • Genotype-phenotype relationship between loss- and gain-of-function patients not fully delineated
    • Neural target genes driving phenotypes not pinpointed
  14. 2025 Medium

    Refined the catalytic division of labor by showing EZH1 uniquely sustains H3K27me1 at Polycomb regions resistant to EZH2-selective inhibitors, with dual inhibition needed to fully erase H3K27 methylation and rewire H3K27ac, and detailed the Q571R gain-of-function biochemistry.

    Evidence ChIP-seq/proteomics with selective versus dual EZH1/2 inhibitors and p300/CBP profiling (preprint), and reconstituted PRC2-EZH1 Q571R enzyme assays with epigenomic profiling (preprint)

    PMID:41000734

    Open questions at the time
    • Functional consequence of residual H3K27me1 not fully established in cells
    • Q571R findings remain preprint and await peer review

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EZH1 selects between repressive H3K27-methylation, SAM-independent compaction, non-histone methylation, and methylation-independent gene activation at a given locus, and what governs its turnover, remains unresolved.
  • No unifying model for context-specific mode selection
  • EZH1 protein stability regulation supported only by single low-confidence Co-IP studies (TRIM21, DNMT1)
  • Cytoplasmic stress-sensing isoform signaling input unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
AML1-ETODNMT1EEDFOXH1SUZ12TRIM21UXT
Complex memberships
PRC2 (noncanonical PRC2-EZH1)

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 EZH1 functions as a histone H3K27 methyltransferase in vivo and in vitro, physically present in a noncanonical PRC2 complex. It colocalizes with the H3K27me3 mark on chromatin and preferentially preserves H3K27me3 on development-related genes in Ezh2-null ESCs. Depletion of Ezh1 in Ezh2-null cells abolishes residual H3K27 methylation and derepresses H3K27me3 target genes. In vitro methyltransferase assay, Co-IP, ChIP, genetic knockdown/knockout in ESCs Molecular cell High 19026780
2008 PRC2-EZH1 performs H3K27 di- and trimethylation weakly compared to PRC2-EZH2. Instead, PRC2-EZH1 directly and robustly represses transcription from chromatinized templates and compacts chromatin in the absence of the methyltransferase cofactor SAM, as demonstrated by electron microscopy. EZH1 is more abundant in nonproliferative adult organs while EZH2 is associated with proliferation. In vitro transcription repression assay on chromatinized templates, electron microscopy for chromatin compaction, knockdown studies for H3K27me2/3 levels Molecular cell High 19026781
2011 Genome-wide analysis reveals Ezh1 complex associates with active epigenetic marks (H3K4me3) and RNA polymerase II. Ezh1 depletion reduces global Pol II occupancy within gene bodies and delays transcriptional activation during skeletal muscle cell differentiation, while overexpression rescues Pol II occupancy defects, indicating a role for Ezh1 in promoting RNA Pol II elongation. Genome-wide ChIP-seq, Pol II ChIP, siRNA knockdown, overexpression in differentiating muscle cells Molecular cell High 22196887
2011 During skeletal muscle differentiation, PRC2-EZH2 occupies the myogenin (MyoG) promoter in proliferating myoblasts and is replaced by PRC2-EZH1 in post-mitotic myotubes. The displacement of PRC2-EZH2 is regulated by Msk1-dependent H3S28 phosphorylation, while this pathway does not affect PRC2-EZH1 binding. Depletion of Ezh1 impairs muscle differentiation and chromatin recruitment of MyoD to the MyoG promoter. ChIP, siRNA knockdown, immunofluorescence in differentiating C2C12 cells Epigenetics & chromatin High 21892963
2012 Ezh1 ablation in adult hematopoietic stem cells (HSCs) causes significant loss of HSCs and impaired self-renewal due to senescence. Epigenomic analysis demonstrates Ezh1-mediated PRC2 activity catalyzes H3K27 monomethylation and dimethylation. Deletion of Cdkn2a on the Ezh1-null background rescues HSC proliferation and survival, placing Ezh1 upstream of Cdkn2a in HSC maintenance. Conditional knockout mice, ChIP-seq (H3K27me1/2/3), transplantation assays, epistasis (Ezh1/Cdkn2a double KO) Cell stem cell High 23122289
2013 UNC1999, a SAM-competitive inhibitor with high potency for both wild-type and mutant EZH2 and EZH1, potently reduces H3K27me3 levels in cells. The mechanism of inhibition is competitive with the cofactor SAM and non-competitive with the peptide substrate. In vitro enzyme inhibition assays, cell-based H3K27me3 measurement, pull-down with biotin-tagged compound ACS chemical biology High 23614352
2015 Ezh1 promotes TLR-triggered inflammatory cytokine production in dendritic cells and macrophages by suppressing the expression of the TLR negative regulator Tollip. Ezh1 directly targets the proximal promoter of Tollip and maintains high H3K27me3 levels there; the SET domain (methyltransferase activity) of Ezh1 is required for this function. siRNA knockdown, ChIP at Tollip promoter, H3K27me3 ChIP, SET domain mutant rescue experiments, cytokine measurement Journal of immunology Medium 25687760
2016 The recurrent EZH1 mutation p.Gln571Arg (Q571R) causes increased histone H3 trimethylation and increased proliferation of thyroid cells, acting as a gain-of-function mutation. EZH1 mutations in autonomous thyroid adenomas are strongly associated with concurrent TSHR or GNAS mutations, suggesting a two-hit model. Whole-exome sequencing, targeted sequencing, functional cell-based assays measuring H3K27me3 and proliferation with EZH1-Q571R expression The Journal of clinical investigation Medium 27500488
2016 EZH1 physically interacts with UXT and SUZ12, forming a complex that positively regulates NF-κB target gene transcription. EZH1 and SUZ12 regulate recruitment of p65 and RNA Pol II to NF-κB target genes without affecting H3K27 methylation at these loci, and EZH1 deficiency increases TNFα-induced cell death. Co-IP, ChIP-seq, RNA interference, reporter assays Journal of cell science Medium 27127229
2017 A novel cytoplasmic isoform of Ezh1 (Ezh1β) lacks the catalytic SET domain and acts in the cytoplasm of skeletal muscle cells to control nuclear PRC2-Ezh1 activity in response to atrophic oxidative stress, by regulating EED assembly with SUZ12 and Ezh1α (the canonical isoform) at target genes. Isoform cloning, fractionation (cytoplasmic vs nuclear), co-IP for EED/SUZ12 interaction, ChIP in skeletal muscle cells under oxidative stress Nature structural & molecular biology Medium 28346433
2017 EZH1 and EZH2 are functionally redundant in slowly proliferating cells (MPNST precursors) but EZH1's compensatory function is alleviated in more rapidly proliferating cells. In the absence of SUZ12, EZH2 loses interaction with all core and accessory PRC2 subunits except EED and is functionally inert, ruling out a PRC2-independent function of EZH2/EZH1. Genetic knockout, pharmacological inhibition, Co-IP for PRC2 complex assembly Proceedings of the National Academy of Sciences of the United States of America Medium 30867289
2017 In neonatal heart regeneration, Ezh1 is specifically required while Ezh2 is dispensable; cardiac myocyte-specific re-expression of EZH1 but not EZH2 restores neonatal heart regeneration in Ezh1 knockout. Mechanistically, EZH1 occupies and activates genes related to cardiac growth. Cardiac-specific conditional knockout and rescue experiments, ChIP-seq, transcriptome profiling Circulation research Medium 28512107
2017 pVHL-defective ccRCC cells are hyperdependent on the H3K27 methyltransferase EZH1 for survival, due to HIF-dependent increased H3K27 demethylase activity causing reduced H3K27 methylation; targeting EZH1 (by shRNA, CRISPR, or pharmacological inhibitor) selectively kills pVHL-deficient cells. Focused shRNA library screen, CRISPR/Cas9 knockout, pharmacological inhibition, H3K27 acetylation/methylation measurement Science translational medicine Medium 28701475
2018 EZH1 represses haematopoietic multipotency in the early mammalian embryo: reduced EZH1 expression enhances multi-lymphoid output from human pluripotent stem cells in vitro, and Ezh1 deficiency in mouse embryos results in precocious emergence of functional definitive HSCs in vivo. shRNA knockdown in human iPSC differentiation, Ezh1 germline knockout mouse, in vivo hematopoietic progenitor functional assays Nature High 29342143
2019 EZH1 methylates the non-histone substrate AML1-ETO at lysine 43 (Lys43) via its SET domain. The EZH1 WD domain binds to the AML1-ETO NHR1 domain, and Lys43 methylation augments AML1-ETO-dependent transcriptional repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO repressive activity. Co-IP (WD-NHR1 domain interaction), in vitro methylation assay, point mutation and domain deletion analysis, transcriptional reporter assays, xenograft models Nature communications High 31699991
2019 EZH1 and EZH2 function primarily within canonical PRC2. EZH1/2 exhibit proliferation-dependent functional redundancy: EZH1 compensates for EZH2 in slowly proliferating cells but not in rapidly proliferating cells. Genetic epistasis (conditional KO), pharmacological inhibition, ChIP-seq Proceedings of the National Academy of Sciences of the United States of America Medium 30867289
2021 Cryo-EM structures of PRC2:EZH1 were solved as a monomer and as a dimer bound to nucleosome. When bound to nucleosome, PRC2:EZH1 dimer undergoes dramatic conformational change. Mutation of a divergent EZH1/2 loop abrogates nucleosome-binding and methyltransferase activities of PRC2:EZH1. PRC2:EZH1 dimers are more effective than monomers at chromatin compaction, and the divergent EZH1/2 loop is essential for both chromatin compaction and methyltransferase activity. Cryo-EM structure determination, site-directed mutagenesis, in vitro methyltransferase assay, nucleosome-binding assay, electron microscopy chromatin compaction assay Nature communications High 33514705
2021 The lncRNA Malat-1 is a necessary partner for PRC2-EZH1-dependent response to oxidative stress in skeletal muscle cells. PRC2-EZH1 dynamic assembly (EED shuttling to nucleus) and stress-induced gene repression depend specifically on Malat-1. Co-IP (PRC2-EZH1 and Malat-1 interaction), knockdown of Malat-1, ChIP in oxidative-stress treated myotubes Cell death & disease Medium 34531374
2021 In zebrafish, Ezh1 loss promotes acquisition of hemogenic (gata2b) and HSPC (runx1) fate at the expense of the arterial program, while Ezh1 overexpression blocks hematopoietic progression. Ezh2 functions non-redundantly and sequentially after Ezh1, with Ezh2 inhibition blocking Ezh1-knockdown-associated HSPC expansion but having no impact on arterial identity. Morpholino knockdown, genetic mutants, overexpression, scRNA-seq in zebrafish embryos Stem cell reports Medium 34143974
2022 EZH1 repression facilitates in vitro differentiation and maturation of T cells from iPSCs. EZH1 acts as a negative regulator of lymphoid potential during embryonic hematopoiesis; EZH1-knockdown-mediated epigenetic reprogramming generates iPSC-derived T cells with diverse TCR repertoire, mature molecular signatures, and functional effector/memory subsets. EZH1 shRNA knockdown in iPSC T cell differentiation system, TCR repertoire sequencing, transcriptomic analysis, xenograft functional assays Cell stem cell Medium 35931029
2022 EZH1 loss- and gain-of-function variants cause neurodevelopmental disorders. Recessive variants impair EZH1 expression causing loss of function; dominant missense variants increase methyltransferase activity (gain of function). EZH1 is necessary and sufficient for differentiation of neural progenitor cells in developing chick embryo neural tube. Cellular and biochemical studies of patient variants, in vitro methyltransferase assay, chick embryo neural tube electroporation, human iPSC-derived neural cultures and forebrain organoids Nature communications High 37433783
2023 Polycomb Ezh1 maintains quiescence of murine muscle stem cells (MuSCs) through a non-canonical function: rather than regulating repressive H3K27 methylation, Ezh1 maintains gene expression of the Notch signaling pathway in MuSCs. Selective genetic reconstitution of Notch signaling corrects stem cell number and re-establishes quiescence of Ezh1-/- MuSCs. Genetic knockout, transcriptome profiling, ChIP, Notch pathway genetic rescue by transgene Developmental cell High 37105173
2023 The EZH1 de novo missense variant p.A678G (in the SET domain) acts as a gain-of-function allele causing dramatic loss of H3K27me2 and a corresponding increase in H3K27me3 in Drosophila. This variant leads to stronger homeotic patterning defects than wild-type when overexpressed. Transgenic Drosophila expressing human variant, H3K27me2/me3 immunostaining, phenotypic analysis Genetics Medium 37314226
2019 Mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange genome-wide distribution of each enzyme, establishing restricted chromatin and gene expression signatures in lymphomas. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. ChIP-seq for EZH1/2 genome-wide occupancy, RNA-seq, pharmacological dual inhibition, comparison of EZH2WT/WT vs EZH2 mutant lymphoma models Cell reports Medium 31747604
2017 Quiescent leukemia stem cells (LSCs) express the highest levels of EZH1 and EZH2. Dual genetic deletion of Ezh1/2 in a mouse AML model induces cell cycle progression of quiescent LSCs and differentiation, eradicating AML LSCs. Quiescent LSCs show PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML is more sensitive to chemotherapy. Conditional double KO in mouse AML model, FACS-based LSC quantification, ChIP-seq, Cyclin D overexpression epistasis, patient-derived xenograft Leukemia Medium 28951561
2021 TRIM21 directly interacts with EZH1 protein and markedly decreases EZH1 protein expression levels, reducing EZH1 protein stability in gastric cancer cells. Overexpression of EZH1 abolishes TRIM21's function to restrain cell viability. Co-IP (TRIM21-EZH1 interaction), Western blot for protein levels, loss/gain-of-function in gastric cancer cells Biochemical and biophysical research communications Low 34856418
2010 Ezh1 participates in left-right patterning in medaka by silencing Spaw (Nodal homolog) expression. Ezh1 physically interacts with FoxH1, a Nodal regulator, via co-immunoprecipitation, revealing a mechanism for Ezh1 in LR patterning. Morpholino knockdown in medaka, co-immunoprecipitation (Ezh1-FoxH1 interaction), in situ hybridization Developmental biology Low 20227405
2025 EZH1-dependent H3K27 monomethylation (H3K27me1) is maintained at Polycomb-enriched genomic regions even when EZH2-selective inhibitors deplete H3K27me2/3. Dual EZH1/2 inhibition eliminates all H3K27 methylation states and redistributes p300/CBP-dependent H3K27ac, generating a bivalent chromatin state that enables tumor suppressor gene re-expression. Proteomic and ChIP-seq analyses, H3K27me1/2/3 profiling with EZH2-selective vs dual EZH1/2 inhibitors, p300/CBP ChIP, RNA-seq bioRxivpreprint Medium 41000734
2025 The EZH1 Q571R mutation (recurrent in thyroid cancer) enhances chromatin binding and compaction, stimulates PRC2-EZH1 catalytic activity leading to increased H3K27me3, represses tumor suppressor genes, and efficiently methylates H3K27 in pre-existing H3K36me2/3 nucleosomes. This gain-of-function is EZH1-specific and not fully recapitulated by the corresponding EZH2 Q570R mutation. ChIP-seq, ATAC-seq, H3K27me3 CUT&Tag, in vitro methyltransferase assay with purified PRC2-EZH1 Q571R vs WT, nucleosome binding assay bioRxivpreprint Medium
2019 EZH1 targets bivalent genes (marked with high H3K27me3 and H2AK119ub1) in HSPCs when Ezh2 is absent, maintaining H3K27me3 specifically at developmental regulator loci (Ezh1 core target genes) in MDS stem cells. ChIP-seq for H3K27me3 and H2AK119ub1 in Ezh1+/-Ezh2Δ/Δ HSPCs, conditional KO mice iScience Medium 30396150
2017 In spermatocytes, only combined loss of EZH1 and EZH2 causes depletion of global H3K27me3 and meiotic arrest. A noncanonical EZH1-PRC2 can establish and maintain H3K27me3 on somatic genes and certain meiotic genes in spermatogenic cells when EZH2-PRC2 is absent. Germline-specific conditional KO (single and double), H3K27me3 ChIP-seq in spermatogenic cells Developmental biology Medium 28254491
2013 In developing hippocampal neurons, Ezh1 and elongation-engaged RNA Polymerase II complexes are present at the PSD-95 (Dlg4) gene promoter. Knockdown of Ezh1 reduces PSD-95 transcription, while Ezh2 knockdown increases it, indicating antagonistic roles. The H3K27me3 mark is absent from the PSD-95 promoter, indicating a methylation-independent role for Ezh1 in transcriptional activation here. siRNA knockdown, ChIP at PSD-95 promoter (Ezh1, Ezh2, Pol II, H3K27me3), RT-PCR in hippocampal neurons Molecular and cellular neurosciences Medium 23932971
2025 EZH1 deficiency reduces H3K27me3 modification at the Nfe2l2 (NRF2) promoter, leading to increased NRF2 expression and nuclear translocation, which promotes ferroptosis resistance in the liver. EZH1 inhibitor DS3201 phenocopies EZH1 knockout, and this anti-ferroptosis effect is reversed by NRF2 inhibitor ML385. EZH1 knockout mice, ChIP for H3K27me3 at Nfe2l2 promoter, pharmacological inhibition with DS3201 and ML385, in vivo sepsis model Clinical epigenetics Medium 40490833
2025 EZH1 promotes TFPI2 promoter DNA methylation by recruiting DNMT1 (co-IP verified), leading to H3K27me3-mediated transcriptional repression of TFPI2, which promotes osteogenic differentiation of periosteum-derived stem cells. EZH1 directly modifies H3K27me3 at the TFPI2 promoter as shown by ChIP-qPCR. Co-IP (EZH1-DNMT1 interaction), ChIP-qPCR (H3K27me3 at TFPI2 promoter), quantitative methylation-specific PCR, adenovirus-mediated overexpression/knockdown Tissue & cell Low 39892329
1996 EZH1 encodes a 747-amino acid protein with 55% amino acid identity to Drosophila E(z), with strongest conservation in the C-terminal SET domain (79% identity) and a conserved cysteine-rich domain. The conserved SET domain is identified as the likely catalytic domain for chromatin/transcriptional regulation. cDNA cloning, protein sequence comparison, transcript analysis (Northern blot) Genomics Low 8921387

Source papers

Stage 0 corpus · 88 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Molecular cell 800 19026780
2008 Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Molecular cell 689 19026781
2013 An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS chemical biology 383 23614352
2011 EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes & development 312 21317239
2014 Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 192 25395428
2012 Ezh1 is required for hematopoietic stem cell maintenance and prevents senescence-like cell cycle arrest. Cell stem cell 171 23122289
2019 Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. Cell reports 161 31747604
2011 Polycomb protein Ezh1 promotes RNA polymerase II elongation. Molecular cell 141 22196887
2015 Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood 125 26219303
2013 Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chemistry & biology 125 24183969
2017 Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer science 120 28741798
2011 Chromatin regulated interchange between polycomb repressive complex 2 (PRC2)-Ezh2 and PRC2-Ezh1 complexes controls myogenin activation in skeletal muscle cells. Epigenetics & chromatin 105 21892963
2013 Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. The EMBO journal 98 23673358
2016 EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy. Nature communications 82 27897169
2017 Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. Leukemia 79 28951561
2022 EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity. Cell stem cell 78 35931029
2018 Regulation of embryonic haematopoietic multipotency by EZH1. Nature 78 29342143
2021 Structures of monomeric and dimeric PRC2:EZH1 reveal flexible modules involved in chromatin compaction. Nature communications 71 33514705
2017 Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 66 28490465
2017 Divergent Requirements for EZH1 in Heart Development Versus Regeneration. Circulation research 65 28512107
2016 Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. The Journal of clinical investigation 62 27500488
2013 Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons. Molecular and cellular neurosciences 59 23932971
2020 Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. PLoS genetics 53 32428001
2018 Clinical utility of EZH1 mutations in the diagnosis of follicular-patterned thyroid tumors. Human pathology 50 29723601
2015 Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip. Journal of immunology (Baltimore, Md. : 1950) 49 25687760
2025 EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models. Cancer cell 46 39983725
2019 EZH1/2 function mostly within canonical PRC2 and exhibit proliferation-dependent redundancy that shapes mutational signatures in cancer. Proceedings of the National Academy of Sciences of the United States of America 46 30867289
2016 Targeting EZH1 and EZH2 contributes to the suppression of fibrosis-associated genes by miR-214-3p in cardiac myofibroblasts. Oncotarget 43 27823969
1996 Characterization of EZH1, a human homolog of Drosophila Enhancer of zeste near BRCA1. Genomics 43 8921387
2017 HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase. Science translational medicine 42 28701475
2017 A cytosolic Ezh1 isoform modulates a PRC2-Ezh1 epigenetic adaptive response in postmitotic cells. Nature structural & molecular biology 38 28346433
2022 The role of EZH1 and EZH2 in development and cancer. BMB reports 35 36476271
2017 EZH1 in germ cells safeguards the function of PRC2 during spermatogenesis. Developmental biology 34 28254491
2016 The EZH1-SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT. Journal of cell science 32 27127229
2019 Polycomb Repressive Complex 2 Proteins EZH1 and EZH2 Regulate Timing of Postnatal Hepatocyte Maturation and Fibrosis by Repressing Genes With Euchromatic Promoters in Mice. Gastroenterology 28 30689973
2021 EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma. Scientific reports 26 34725436
2020 The polycomb proteins EZH1 and EZH2 co-regulate chromatin accessibility and nephron progenitor cell lifespan in mice. The Journal of biological chemistry 26 32554463
2024 A Phase I/II Study of Valemetostat (DS-3201b), an EZH1/2 Inhibitor, in Combination with Irinotecan in Patients with Recurrent Small-Cell Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 25 38940666
2022 Dual targeting of EZH1 and EZH2 for the treatment of malignant rhabdoid tumors. Molecular therapy oncolytics 25 36212776
2021 TRIM21 improves apatinib treatment in gastric cancer through suppressing EZH1 stability. Biochemical and biophysical research communications 25 34856418
2022 Maternal Ezh1/2 deficiency in oocyte delays H3K27me2/3 restoration and impairs epiblast development responsible for embryonic sub-lethality in mouse. Development (Cambridge, England) 22 35796552
2023 Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders. Nature communications 21 37433783
2022 microRNA-27a-3p delivered by extracellular vesicles from glioblastoma cells induces M2 macrophage polarization via the EZH1/KDM3A/CTGF axis. Cell death discovery 21 35568721
2019 Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57CDKN1C and TP53INP1 in mantle cell lymphoma. Cancer biology & medicine 20 31565482
2021 CDKN1C-mediated growth inhibition by an EZH1/2 dual inhibitor overcomes resistance of mantle cell lymphoma to ibrutinib. Cancer science 19 33792119
2019 Ezh1 arises from Ezh2 gene duplication but its function is not required for zebrafish development. Scientific reports 19 30867490
2019 Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia. Nature communications 19 31699991
2018 Ezh1 Targets Bivalent Genes to Maintain Self-Renewing Stem Cells in Ezh2-Insufficient Myelodysplastic Syndrome. iScience 19 30396150
2022 Valemetostat: First approval as a dual inhibitor of EZH1/2 to treat adult T-cell leukemia/lymphoma. Drug discoveries & therapeutics 18 36310058
2021 LncRNA SNHG3 is responsible for the deterioration of colorectal carcinoma through regulating the miR-370-5p/EZH1 axis. European review for medical and pharmacological sciences 17 34661273
2021 Malat-1-PRC2-EZH1 interaction supports adaptive oxidative stress dependent epigenome remodeling in skeletal myotubes. Cell death & disease 16 34531374
2021 Long Noncoding RNA PRNCR1 Reduces Renal Epithelial Cell Apoptosis in Cisplatin-Induced AKI by Regulating miR-182-5p/EZH1. Kidney & blood pressure research 15 33647908
2021 Sequential regulation of hemogenic fate and hematopoietic stem and progenitor cell formation from arterial endothelium by Ezh1/2. Stem cell reports 15 34143974
2023 EZH1/2 dual inhibitors suppress HTLV-1-infected cell proliferation and hyperimmune response in HTLV-1-associated myelopathy. Frontiers in microbiology 13 37378292
2019 The Effect of Overexpression of the Enhancer of Zeste Homolog 1 (EZH1) Gene on Aristolochic Acid-Induced Injury in HK-2 Human Kidney Proximal Tubule Cells In Vitro. Medical science monitor : international medical journal of experimental and clinical research 12 30688289
2018 EZH1 Is Associated with TCP-Induced Bone Regeneration through Macrophage Polarization. Stem cells international 12 30228822
2023 A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster. Genetics 11 37314226
2022 Mitochondria-targeting nano therapy altering IDH2-mediated EZH2/EZH1 interaction as precise epigenetic regulation in glioblastoma. Biomaterials science 11 35917200
2019 MicroRNA-765 alleviates the malignant progression of breast cancer via interacting with EZH1. American journal of translational research 11 31396353
2018 EZH1 is an antipsychotic-sensitive epigenetic modulator of social and motivational behavior that is dysregulated in schizophrenia. Neurobiology of disease 11 30099093
2021 EZH1/2 Inhibitors Favor ILC3 Development from Human HSPC-CD34+ Cells. Cancers 10 33467134
2023 Polycomb Ezh1 maintains murine muscle stem cell quiescence through non-canonical regulation of Notch signaling. Developmental cell 9 37105173
2022 Dual inhibition of EZH1/2 induces cell cycle arrest of B cell acute lymphoblastic leukemia cells through upregulation of CDKN1C and TP53INP1. International journal of hematology 9 36280659
2022 Polycomb EZH1 regulates cell cycle/5-fluorouracil sensitivity of neuroblastoma cells in concert with MYCN. Cancer science 8 36052716
2016 Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms. Pathology 8 27311868
2021 MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1. Frontiers in oncology 7 34976797
2010 Polycomb group protein Ezh1 represses Nodal and maintains the left-right axis. Developmental biology 6 20227405
2025 Reduced EZH1/2 expression in imipridone-treated cells correlates with synergy following combinations with EZH1/2 or HDAC inhibitors in diffuse glioma and other tumors. American journal of cancer research 5 40226473
2021 Ezh1 regulates expression of Cpg15/Neuritin in mouse cortical neurons. Drug discoveries & therapeutics 5 33678755
2024 The competitive mechanism of EZH1 and EZH2 in promoting oral squamous cell carcinoma. Experimental cell research 4 38309675
2024 Clinical Significance of Upregulation of EZH1 Expression in Hepatocellular Carcinoma Tissues. Journal of gastrointestinal and liver diseases : JGLD 4 38554427
2012 A new role for the polycomb group protein Ezh1 in promoting transcription. Molecular cell 4 22284674
2025 EZH1 deficiency promotes ferroptosis resistance by activating NRF2 in sepsis-associated liver injury. Clinical epigenetics 3 40490833
2024 Maternal Ezh1/2 deficiency impairs the function of mitochondria in mouse oocytes and early embryos. Journal of cellular physiology 3 38529784
2024 A novel EZH1/2 dual inhibitor inhibits GCB DLBCL through cell cycle regulation and M2 tumor-associated macrophage polarization. The Journal of biological chemistry 3 39303914
2024 EZH1/2 plays critical roles in oocyte meiosis prophase I in mice. Biological research 3 39511641
2025 EZH1-DNMT1 axis inhibits the expression of TFPI2 to promote osteogenic differentiation of periosteum-derived stem cells and accelerate fracture repair. Tissue & cell 2 39892329
2024 Unlocking adult T-cell leukemia/lymphoma's epigenetic secrets: delving into the mechanism and impact of EZH1/2 inhibition. Immunology and cell biology 2 38606590
2024 CircRBM33 competitively binds miR-15a-5p to mediate EZH1 expression to ameliorate sepsis-induced acute lung injury. Clinics (Sao Paulo, Brazil) 2 39667201
2023 miR-424(322)-5p targets Ezh1 to inhibit the proliferation and differentiation of myoblasts. Acta biochimica et biophysica Sinica 2 36988349
2023 Dynamic Interactome of PRC2-EZH1 Complex Using Tandem-Affinity Purification and Quantitative Mass Spectrometry. Methods in molecular biology (Clifton, N.J.) 1 37212992
2021 Development of a UPLC-MS/MS method for determination of a dual EZH1/2 inhibitor UNC1999 in rat plasma. Bioanalysis 1 34841882
2018 Reversing Time: Ezh1 Deficiency Hastens Definitive Hematopoiesis. Cell stem cell 1 29499144
2018 [Epigenetic aberrations in adult T-cell leukemia/lymphoma and development of a novel EZH1/2 inhibitor]. [Rinsho ketsueki] The Japanese journal of clinical hematology 1 29743404
2025 Dual EZH1/2 inhibition enhances DNMT inhibitor efficacy in colon cancer through targeting H3K27me1. bioRxiv : the preprint server for biology 0 41000734
2025 EZH1 Inhibition attenuates apoptosis and promotes regeneration for liver repair in acute liver failure. BMC gastroenterology 0 41286609
2023 A de novo missense variant in EZH1 associated with developmental delay exhibits functional deficits in Drosophila melanogaster. medRxiv : the preprint server for health sciences 0 36778246
2023 A Combination of BRAF and EZH1/SPOP/ZNF148 Three-Gene Mutational Classifier Improves Benign Call Rate in Indeterminate Thyroid Nodules. Endocrine pathology 0 37572175

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