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Showing EHMT2 — G9A is a alias.

EHMT2

Histone-lysine N-methyltransferase EHMT2 · UniProt Q96KQ7

Length
1210 aa
Mass
132.4 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EHMT2 (G9a) is a SET-domain histone lysine methyltransferase that operates predominantly as a G9a-GLP heterodimer, the principal enzyme generating H3K9me1 and H3K9me2 in euchromatin (PMID:21498567); heterodimerization relieves autoinhibition and enhances both H3K9me2 recognition and catalytic turnover roughly 10-fold over homodimers on nucleosomes (PMID:34619147). It couples H3K9 methylation to DNA methylation by binding DNMT1 and forming a ternary complex with PCNA at replication foci, and by establishing H3K9me2/HP1 platforms that recruit de novo DNA methyltransferases to silence target promoters (PMID:17085482, PMID:18809684); catalytic and DNA-methylation-dependent silencing are mechanistically separable, and several G9a functions—including protection of imprinted DNA methylation and transcriptional co-activation—are independent of its catalytic activity (PMID:18818694, PMID:27052169). Through these activities G9a controls developmental and lineage programs, silencing germline, meso-endodermal, and cardiac genes and protecting maternal and imprinted DNA from TET-mediated demethylation (PMID:26576615, PMID:28778944, PMID:31088968, PMID:36604593), and restraining Th17/Treg differentiation in naive T cells (PMID:24667637). Beyond histones, G9a methylates non-histone substrates including histone H1 variants (H1.4K26, H1.2K187), FOXO1-K273 to drive its SKP2-dependent degradation, and GMFB-K25 (PMID:19144645, PMID:20334638, PMID:30535125, PMID:37307824). G9a is regulated by signaling and post-translational modification: CK2- and ATM-dependent phosphorylation recruit it to DNA double-strand breaks to promote RPA/Rad51 loading and homologous recombination (PMID:28698370, PMID:29192276), SUMOylation activates its PCAF-dependent co-activator function at E2F1 targets (PMID:30867409), prolyl hydroxylation controls its stability under hypoxia (PMID:28630300), and SPOP-mediated ubiquitination of its partner GLP governs heterodimer abundance (PMID:34588438). It further acts as a scaffold within complexes containing Mediator, EZH2/PRC2 (via PALI1), CHD4, MEF2C, and ZFP462 to coordinate H3K9 and H3K27 methylation and shape transcriptional programs in development and cancer (PMID:23112189, PMID:28778944, PMID:36604593, PMID:36476474, PMID:38065340). In tumors G9a drives oncogenic programs by silencing WNT antagonists (DKK1, APC, SFRP1) and tumor suppressors and by stabilizing c-Myc (PMID:32269030, PMID:34344448, PMID:36896891, PMID:38814866).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 Medium

    Established that the full-length protein is exclusively nuclear and identified a domain controlling its nuclear localization, defining where G9a acts.

    Evidence Epitope-tagged subcellular localization with domain deletion in transfected mammalian cells

    PMID:11707778

    Open questions at the time
    • No functional readout beyond localization
    • Single lab
    • NLS not mapped at residue level
  2. 2006 High

    Showed G9a physically links H3K9 methylation to the DNA replication and methylation machinery, answering how the two epigenetic marks are coordinated.

    Evidence Reciprocal Co-IP, in vitro binding, replication foci colocalization, in vitro chromatin methylation assay

    PMID:17085482

    Open questions at the time
    • Stoichiometry and order of complex assembly at forks unresolved
    • Direct vs DNMT1-bridged PCNA contact not fully separated
  3. 2008 High

    Demonstrated G9a silences genes through two separable routes—H3K9 methylation and DNA methylation—revealing a catalytic-independent silencing arm.

    Evidence Catalytic-inactive mutant reconstitution in ES cells with DNMT inhibitor and expression readouts; ChIP/siMethylation in tolerant cells

    PMID:18809684 PMID:18818694

    Open questions at the time
    • Catalytic-independent DNA methylation recruitment mechanism not defined
    • TNFa promoter cascade from single lab
  4. 2010 High

    Identified histone H1 variants as direct G9a substrates, extending its writing activity beyond core histones and defining variant-specific reader outcomes.

    Evidence In vitro and in vivo methyltransferase assays with site-specific antibodies and HP1/L3MBTL1 binding analysis

    PMID:19144645 PMID:20334638

    Open questions at the time
    • In vivo functional consequences of H1.2K187 methylation limited
    • Cooperativity with histone substrate methylation unclear
  5. 2012 High

    Placed G9a within distinct activating (Mediator) and repressive (Jarid1a) complexes and as a PKA effector controlling differentiation timing, showing context-dependent dual function.

    Evidence Co-IP, ChIP, genetic erythroid model; G9a KO ESC with PKA activation and epistasis

    PMID:22704517 PMID:23112189

    Open questions at the time
    • Switch between activating and repressive complexes not mechanistically defined
    • Mediator-G9a interface unmapped
  6. 2015 Medium

    Confirmed genome-wide that G9a directs DNA methylation and silencing at germline-gene promoters in embryos and interacts with EZH2 to drive EMT, linking H3K9 and H3K27 pathways.

    Evidence Ehmt2 KO mouse with genome-wide methylation and ChIP; Co-IP/ChIP in pancreatic cancer cells

    PMID:26576615 PMID:26688070

    Open questions at the time
    • Direct vs indirect EZH2 cooperation not separated
    • Locus-selection determinants unknown
  7. 2016 High

    Revealed catalytic-independent and isoform-dependent layers: protection of imprinted DNA methylation without H3K9me2, splice-driven nuclear localization, and human-specific p53 co-activation.

    Evidence G9a/GLP KO and catalytic-mutant ESCs with allele-specific methylation; alternative splicing/fractionation; Co-IP and reporter assays for p53/p300

    PMID:26997278 PMID:27052169 PMID:27452519

    Open questions at the time
    • Mechanism by which the complex recruits de novo DNMTs catalytically-independently unresolved
    • Species divergence in p53 regulation unexplained
  8. 2017 High

    Established G9a as a phosphorylation-regulated DNA repair factor and defined post-translational and complex-based controls over its stability and tissue function.

    Evidence CK2/ATM phospho-site mapping, RPA/Rad51 and 53BP1/BRCA1 foci, HR assays; prolyl hydroxylation stability assays; cardiac conditional KO with ChIP-seq/RNA-seq and MEF2C/EZH2 Co-IP; Notch rescue in placenta

    PMID:28455378 PMID:28630300 PMID:28698370 PMID:28778944 PMID:29192276

    Open questions at the time
    • Whether DSB recruitment requires catalytic activity vs scaffolding partly conflicting
    • Substrates methylated at break sites not fully defined
  9. 2019 High

    Expanded the non-histone substrate and regulatory repertoire (FOXO1-K273 degradation, SUMO-driven PCAF co-activation) and detailed fibrosis and chromatin-loop functions.

    Evidence In vitro methylation and SKP2 Co-IP; SUMO site mutagenesis with myoblast complementation and ChIP; cyclin D1 Co-IP/ChIP/LAD analysis; G9a-CBX5 ChIP in fibrosis models; EZH2 interplay by PLA/Re-ChIP

    PMID:29053336 PMID:30535125 PMID:30718920 PMID:30867409 PMID:31088968 PMID:31095524 PMID:31647887

    Open questions at the time
    • Generality of non-histone methylation across tissues untested
    • How SUMO toggles activator vs repressor states unresolved
  10. 2020 High

    Defined G9a's genome-architectural role and its oncogenic gain-of-function, showing it shapes chromatin accessibility/looping and drives WNT-dependent tumor growth and immune exclusion.

    Evidence ATAC-seq/ChIP-seq/Hi-C in depletion and catalytic-mutant ESCs; oncogenic mutation analysis with ChIP and in vivo melanoma models; recurrent tumor genetic ablation with necroptosis readouts

    PMID:32269030 PMID:33113380 PMID:33147463

    Open questions at the time
    • Mechanism connecting H3K9me2 loss to altered CTCF/cohesin binding unclear
    • Catalytic vs scaffold contribution to looping not separated
  11. 2021 High

    Resolved the biochemical basis of heterodimer superiority, defined SPOP-GLP-G9a stability control, and broadened oncogenic and substrate repertoire including GMFB methylation.

    Evidence Recombinant dimer reconstitution with nucleosomes and XL-MS; SPOP Co-IP/ubiquitination/methylome/xenografts; in vitro GMFB methylation with in vivo neuroprotection models; APC/ERVK ChIP in KO models

    PMID:34344448 PMID:34519223 PMID:34588438 PMID:34619147 PMID:37307824

    Open questions at the time
    • Structural model of full heterodimer absent
    • In vivo mutagenesis validation for GMFB-K25 limited
  12. 2022 High

    Established scaffolding super-complexes (PALI1-PRC2, ZFP462, CHD4) coordinating dual H3K9/K27 methylation and immune evasion, and delivered first covalent G9a/GLP inhibitors with a crystallographic binding mode.

    Evidence Co-IP and ChIP-seq for PALI1 and ZFP462 complexes in cancer and ESC KO models; CRISPR screen and Co-IP for CHD4; covalent inhibitor synthesis with X-ray structure and cellular H3K9me2 assays

    PMID:35763668 PMID:36476474 PMID:36604593 PMID:38065340

    Open questions at the time
    • Determinants selecting dual-methylation target subsets unknown
    • G9a vs GLP selectivity of covalent inhibitors only partial
  13. 2023 Medium

    Extended oncogenic mechanisms to Notch activation via Fbxw7 silencing and c-Myc stabilization, reinforcing G9a as a transcriptional and protein-stability hub in cancer.

    Evidence ChIP/luciferase in glioma stem cells with immune profiling; c-Myc/G9a Co-IP and PDX models

    PMID:36896891 PMID:36971192

    Open questions at the time
    • Whether c-Myc stabilization is methylation-dependent unresolved
    • Single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • How G9a is targeted to specific genomic loci across its many partner-defined complexes, and what distinguishes its catalytic from scaffolding contributions at each target, remains the central unresolved question.
  • No unified model of locus selection across Mediator/PRC2/CHD4/ZFP462 contexts
  • Catalytic vs scaffold contribution not systematically dissected genome-wide
  • Structural basis of heterodimer at nucleosomes incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2 R-HSA-73894 DNA Repair 2
Partners
CHD4DNMT1EZH2GLPMEF2CPCNARPAZFP462
Complex memberships
G9a-DNMT1-PCNA ternary complexG9a-GLP heterodimerG9a-Mediator complexG9a-PALI1-PRC2 super-complex

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 G9a and GLP exist predominantly as a G9a-GLP heteromeric complex that is the primary functional H3K9 methyltransferase in vivo, responsible for H3K9me1 and H3K9me2 in euchromatin. Biochemical characterization, genetic knockout studies in mammalian cells Genes & development High 21498567
2006 EHMT2/G9a directly binds DNMT1 both in vivo and in vitro, colocalizes with DNMT1 at replication foci during DNA replication, and together with DNMT1 forms a ternary complex with PCNA on chromatin; this complex enhances both DNA and H3K9 methylation of in vitro assembled chromatin substrates. Co-immunoprecipitation, in vitro binding assay, colocalization studies, siRNA knockdown, in vitro chromatin methylation assay Genes & development High 17085482
2008 G9a/GLP complex suppresses transcription by independently inducing both H3K9 methylation and DNA methylation; catalytically inactive G9a/GLP mutants fail to rescue H3K9 methylation but still support DNA methylation-dependent gene silencing, demonstrating two distinct silencing mechanisms. ES cell catalytic mutant analysis, DNA methyltransferase inhibitor treatment, gene expression analysis The EMBO journal High 18818694
2009 G9a/KMT1C mediates mono- and dimethylation of histone H1.4 at lysine 26 (H1.4K26) in vitro and in vivo, providing a recognition surface for HP1 and L3MBTL1; G9a also promotes H1 deposition and is required for retention of H1 on chromatin. In vitro methyltransferase assay, in vivo ChIP, H1.4K26 methylation-specific antibodies, H1 chromatin retention assays The Journal of biological chemistry High 19144645
2010 G9a/KMT1C and GLP1/KMT1D methylate histone H1.2 at lysine 187 (H1.2K187) in its C-terminus in vitro and in vivo; this methylation is variant-specific and distinct from H1.4K26 methylation in that it cannot recruit HP1 and is not reversed by JMJD2D/KDM4. In vitro methyltransferase assay, in vivo cell-based methylation analysis, HP1 binding assays, cell cycle analysis Epigenetics & chromatin High 20334638
2008 G9a binds the TNFα promoter in endotoxin-tolerant cells, dimethylates H3K9 creating a platform for HP1 binding, which recruits DNMT3a/b causing promoter CpG methylation and transcriptional silencing; G9a knockdown disrupts this silencing cascade. ChIP, RNA interference/siRNA knockdown, CpG methylation analysis The Journal of biological chemistry Medium 18809684
2010 LSH (encoded by Hells) is required for G9a/GLP complex recruitment to specific loci; in Hells-/- MEFs, G9a recruitment is compromised, impairing stable gene silencing and DNA methylation at specific promoters through a cooperative LSH–G9a/GLP mechanism. Genome-wide DNA methylation profiling, ChIP, Hells knockout MEFs Genome research Medium 21149390
2012 G9a functions within two distinct protein complexes: one containing the coactivator Mediator (for gene activation) and one containing the H3K4 demethylase Jarid1a/KDM5A (for gene repression); repressive function requires coordinate action of G9a-mediated H3K9me2/H3K27me2 and Jarid1a-mediated removal of H3K4me3. Co-immunoprecipitation, ChIP, genetic analysis in erythroid differentiation model Proceedings of the National Academy of Sciences of the United States of America Medium 23112189
2012 G9a mediates H3K9 dimethylation and DNA methylation at the Oct3/4 and Nanog promoters downstream of protein kinase A (PKA) signaling; G9a deletion abolishes PKA-driven acceleration of ESC differentiation, placing G9a as a PKA effector controlling differentiation timing. G9a knockout ESC/mouse model, PKA activation experiments, ChIP, bisulfite sequencing Cell stem cell High 22704517
2015 EHMT2 binds specific genomic loci in embryonic cells (including CpG-rich promoters of germline-specific genes), is marked by H3K9me2, and is required for DNA methylation at these loci; EHMT2-mediated DNA methylation is instrumental for gene silencing at these loci during embryogenesis. Ehmt2 knockout mouse model, genome-wide DNA methylation analysis, ChIP Genome research High 26576615
2016 G9a exists as two isoforms distinguished by alternative splicing of exon 10 (E10); E10 inclusion increases G9a nuclear localization and overall H3K9me2 levels without affecting catalytic activity, and the E10+ isoform is necessary for neuronal differentiation; G9a promotes E10 inclusion creating a positive feedback loop. Alternative splicing analysis, nuclear/cytoplasmic fractionation, H3K9me2 measurement, neuronal differentiation assays, G9a knockdown Cell reports Medium 26997278
2016 G9a blocks myogenic cell cycle exit via methylation-dependent transcriptional repression of p21(Cip/Waf1) and Rb1 (MyoD target genes), and activates E2F1-target genes in a methyltransferase activity-independent manner by associating with the E2F1/PCAF complex to enhance PCAF occupancy and histone acetylation at E2F1-target promoters. ChIP, Co-immunoprecipitation, G9a knockdown, transcriptome analysis, cell cycle assays Nucleic acids research Medium 27229136
2017 In response to DNA double-strand breaks, G9a is phosphorylated at serine 211 by casein kinase 2 (CK2), recruited to chromatin, and directly interacts with the replication protein A (RPA) complex to promote RPA and Rad51 loading at DSBs, facilitating homologous recombination repair. Phosphorylation mapping, Co-immunoprecipitation, RPA foci formation assays, HR repair assays, CK2 inhibition Proceedings of the National Academy of Sciences of the United States of America High 28698370
2017 ATM phosphorylates G9a on serine 569, which is required for its recruitment to DNA breaks; G9a catalytic activity is required for early recruitment of DNA repair factors 53BP1 and BRCA1 to DNA breaks. Phosphorylation site mutation, DNA damage foci analysis, G9a catalytic inhibition, ionizing radiation sensitivity assays Scientific reports Medium 29192276
2017 G9a protein stability is increased under hypoxia via reduced proline hydroxylation leading to inefficient proteasomal degradation, resulting in increased H3K9me2 at target promoters and repression of specific genes. Protein stability assays, proline hydroxylation analysis, proteasome inhibition, ChIP, in vitro and in vivo tumor growth assays Proceedings of the National Academy of Sciences of the United States of America Medium 28630300
2017 G9a forms a complex with MEF2C transcription factor in cardiomyocytes and represses key cardiac function genes via H3K9me2; G9a also interacts with EZH2 (PRC2 catalytic subunit) and is required for maintenance of heterochromatin and silencing of developmental genes in the adult heart. Conditional cardiac-specific G9a KO mouse, ChIP-seq, RNA-seq, Co-immunoprecipitation Circulation High 28778944
2019 G9a methylates FOXO1 at K273 in vitro and in vivo; this methylation increases FOXO1 interaction with E3 ligase SKP2, decreasing FOXO1 protein stability and promoting colon cancer cell proliferation; insulin increases G9a expression, resulting in insulin-mediated FOXO1 degradation via K273 methylation. In vitro methylation assay, Co-immunoprecipitation, protein stability assay, proliferation and apoptosis assays Nucleic acids research High 30535125
2015 G9a (EHMT2) promotes H3K27 methylation by upregulating PCL3 (increasing PRC2 promoter recruitment) and downregulating H3K27 demethylase KDM7A; G9a physically interacts with EZH2 to repress E-cadherin expression and induce EMT in pancreatic cancer cells. Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression experiments Scientific reports Medium 26688070
2016 G9a interacts with human G9a (hG9a) but unlike mouse G9a, human G9a potently stimulates p53 transcriptional activity independent of its methyltransferase activity; hG9a interacts with histone acetyltransferase p300/CBP resulting in increased histone acetylation at the Puma promoter. Co-immunoprecipitation, ChIP, luciferase reporter, shRNA knockdown, apoptosis and colony assays Oncogene Medium 27452519
2019 SUMOylation of G9a at K79, K152, K256, and K799 is required for its function as an activator of myoblast proliferation; SUMOylation acts as a signal for PCAF recruitment at E2F1-target genes, increasing H3K9 acetylation and S-phase progression, but does not affect G9a-mediated repression of MyoD activity. SUMOylation site mutagenesis, complementation assays in G9a conditional KO primary myoblasts, ChIP, cell cycle analysis Cell death & disease High 30867409
2019 EHMT2/G9a and EZH2 physically interact with each other at the CXCL10 promoter in IPF fibroblasts; EZH2 knockdown reduces G9a and H3K9me3, and G9a knockdown reduces EZH2 and H3K27me3, demonstrating a functionally interdependent interplay mediating epigenetic repression of CXCL10. ChIP, Re-ChIP, proximity ligation assay, siRNA knockdown American journal of respiratory cell and molecular biology Medium 29053336
2019 G9a promotes H3K9me2-dependent silencing of pro-inflammatory cytokines (including TNF) in recurrent mammary tumors; G9a-mediated silencing suppresses necroptosis and tumor recurrence. G9a genetic ablation, ChIP, gene expression analysis, cell death assays in recurrent tumor models Cell reports Medium 33147463
2020 G9a regulates chromatin accessibility, epigenetic modifications, and transcriptional silencing in both catalytic-dependent and catalytic-independent manners; loss of G9a leads to altered CTCF and cohesin binding and differential chromatin looping, especially at retrotransposons, while topologically associated domains are largely unaffected. G9a depletion and catalytic mutant ESC lines, ATAC-seq, ChIP-seq, RNA-seq, Hi-C Cell reports High 33113380
2020 G9a gain-of-function mutations and copy number gains in melanoma suppress WNT antagonist DKK1 expression through H3K9me2-mediated promoter methylation, activating WNT/β-catenin signaling and driving tumor growth and immune exclusion. Oncogenic G9a mutation identification, ChIP, genetic/pharmacologic G9a suppression in vitro and in vivo tumor models Cancer discovery Medium 32269030
2021 SPOP E3 ligase binds GLP and promotes its polyubiquitination and proteasomal degradation; SPOP mutation stabilizes GLP and its partner G9a, leading to aberrant global DNA hypermethylation and silencing of tumor suppressor genes in prostate cancer. Co-immunoprecipitation, ubiquitination assay, SPOP mutant cell lines, genome-wide DNA methylome analysis, xenograft models Nature communications High 34588438
2021 Heterodimerization of G9a and GLP (heterodimer) significantly enhances both H3K9me2 reading (recognition) and writing (catalytic turnover) activities compared to homodimers; the heterodimer shows ~10-fold increased turnover on nucleosomal substrates; cross-linking mass spectrometry reveals distinct domain contacts between heterodimer vs. homodimers suggesting relieved autoinhibition. Recombinant homodimer/heterodimer production, in vitro methyltransferase assay, nucleosomal substrate assay, cross-linking mass spectrometry The Journal of biological chemistry High 34619147
2016 G9a/GLP complex maintains imprinted DNA methylation at imprinting control regions (ICRs) in ESCs through a catalytic activity-independent mechanism; the complex protects imprinted DNA methylation by recruiting de novo DNA methyltransferases that antagonize TET dioxygenase-dependent erosion, not through H3K9me2. G9a/GLP knockout and catalytic mutant ESCs, allele-specific DNA methylation analysis, TET dioxygenase assays Cell reports High 27052169
2019 EHMT2 and SETDB1 in oocytes provide H3K9me2 and H3K9me3, respectively, to the maternal pronucleus; genetic deletion of the EHMT2 catalytic domain in oocytes reduces H3K9me2 and increases TET3-mediated 5mC oxidation (5hmC, 5fC, 5caC) in the maternal pronucleus, demonstrating that oocyte-derived EHMT2 H3K9 methylation protects maternal DNA from oxidative demethylation. Oocyte-specific conditional KO of EHMT2 catalytic domain, immunofluorescence for 5mC/5hmC/5fC/5caC in zygotes Proceedings of the National Academy of Sciences of the United States of America High 31088968
2019 G9a (EHMT2) is required for TGFβ- and matrix stiffness-induced fibroblast activation; G9a and CBX5 (HP1α) form a repressor complex that deposits H3K9me marks to silence PPARGC1A (PGC1α) expression, sustaining fibroblast activation in pulmonary fibrosis. G9a inhibition and knockdown, ChIP, TGFβ and mechanical stiffness stimulation, bleomycin lung injury model JCI insight Medium 31095524
2017 G9a activates the Notch pathway in placental endothelial progenitors to balance endothelial and trophoblast proliferation; G9a-deficient endothelial progenitors show downregulated Notch effectors including Rbpj, and Notch pathway activation rescues placental vascular defects. Conditional G9a KO in endothelial progenitors, in vivo vascular analysis, Notch activation rescue experiments Development (Cambridge, England) Medium 28455378
2022 ZFP462 (murine homologue of ZNF462) recruits the G9A/GLP complex to transposable element-containing enhancers harbouring pluripotency and meso-endoderm transcription factor binding sites, seeding heterochromatin to restrict transcription factor binding and silence meso-endodermal genes during neural lineage specification. ZFP462 screen and KO in ESCs, ChIP-seq, ATAC-seq, Co-IP showing ZFP462-G9A/GLP interaction Nature cell biology High 36604593
2022 PALI1 interacts with G9A and bridges formation of a G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression, promoting prostate cancer cell proliferation and invasion. Co-immunoprecipitation, ChIP-seq, genetic knockdown, in vitro and xenograft tumor models Molecular cell High 36476474
2019 Cyclin D1 directly associates with G9a and is required for G9a recruitment to target gene chromatin and for G9a-induced H3K9me2; cyclin D1 is also required for nuclear lamina-lamina-associated domain (LAD) interactions dependent on G9a-mediated H3K9me2. Co-immunoprecipitation, ChIP, cyclin D1 genetic requirement assays, LAD interaction analysis Oncogene Medium 30718920
2001 NG36 and G9a are expressed as a single ~3.9 kb transcript in human and mouse cells; the full-length NG36/G9a protein is concentrated exclusively in the nucleus, whereas the G9a region alone (aa 210-1210) localizes to both cytoplasm and nucleus and is marginalized at the nuclear periphery—demonstrating that the NG36 domain controls nuclear localization of the protein. Expression cloning, T7-epitope tagged subcellular localization in transiently transfected mammalian cells, RT-PCR for splice variants Mammalian genome Medium 11707778
2021 G9a directly binds and methylates GMFB (glia maturation factor β) at lysine 20 and K25 in vitro; methylation at K25 suppresses GMFB neuroprotective activity; G9a pharmacological inhibition removes K25 methylation, increasing GMFB activity and promoting neuroprotective effects in Alzheimer's disease models. In vitro methylation assay identifying K20 and K25, ChIP-seq after G9a inhibition, pharmacological inhibition in mouse model and C. elegans Aging and disease Medium 37307824
2019 G9a promotes mTOR expression through H3K9 monomethylation at the mTOR promoter (not dimethylation); G9a knockdown decreases H3K9 monomethylation at the mTOR promoter and reduces mTOR expression, thereby suppressing gastric cancer cell proliferation and inducing autophagy. ChIP analysis of H3K9me1/me2 at mTOR promoter, G9a siRNA and inhibitor treatment, mTOR rescue experiments FASEB journal Medium 31647887
2021 EHMT2 controls H3K9me2 at ERVK (endogenous retrovirus K) promoters on the maternal allele of noncanonical imprinted genes in the ectoplacental cone; in Ehmt2 embryos, loss of H3K9me2 and DNA methylation at ERVK promoters leads to biallelic derepression of noncanonical imprinted genes. Allele-specific RNA-seq in Ehmt2 KO embryos, reciprocal mouse crosses, ERVK promoter methylation analysis Epigenomics Medium 34519223
2023 G9a binds the Fbxw7 promoter and represses its transcription via H3K9me2, thereby activating the Notch pathway and promoting stemness in glioma stem cells and an immunosuppressive tumor microenvironment. ChIP, dual-luciferase reporter assay, G9a inhibition/knockdown, flow cytometry for immune cells in orthotopic model CNS neuroscience & therapeutics Medium 36971192
2022 CHD4 represses galectin-7 expression by recruiting EHMT2 to form a co-transcriptional silencing complex; EHMT2 inhibition disrupts this complex, inducing galectin-7 expression and converting immunosuppressive MSS colorectal cancer to an immunomodulatory state. CRISPR screen, co-immunoprecipitation, ChIP, functional immune co-culture assays Gastroenterology Medium 38065340
2021 EHMT2 directly mediates H3K9me2 methylation of the APC promoter to epigenetically silence APC expression, activating Wnt-β-catenin signaling in hepatocellular carcinoma. EHMT2 CRISPR KO, ChIP for H3K9me2 at APC promoter, rescue experiments with APC overexpression, xenograft assays Cell & bioscience Medium 34344448
2023 c-Myc interacts with G9a in HCC, cooperating to regulate c-Myc-dependent gene repression; G9a stabilizes c-Myc protein to promote cancer growth and invasion. Co-immunoprecipitation, c-Myc/G9a co-expression knockdown and overexpression, xenograft and patient-derived xenograft models Molecular oncology Medium 36896891
2022 EHMT2 increases methylation of the SFRP1 promoter region, reducing SFRP1 expression and activating the WNT/β-catenin pathway to drive neuroendocrine transformation and TKI resistance in lung adenocarcinoma. ChIP for H3K9me2/DNA methylation at SFRP1 promoter, EHMT2 inhibitor rescue, CDX mouse models Proceedings of the National Academy of Sciences of the United States of America Medium 38814866
2022 Discovery of first-in-class covalent G9a/GLP inhibitors targeting a cysteine at the substrate binding site; X-ray crystallography confirmed covalent binding mode; compound 8 (MS8511) showed improved potency over noncovalent inhibitor UNC0642 and potential kinetic preference for G9a over GLP. Covalent inhibitor synthesis, enzymatic assay, mass spectrometry-based covalent modification confirmation, X-ray crystallography, cellular H3K9me2 assay Journal of medicinal chemistry High 35763668
2017 G9a inhibition in the nucleus accumbens (NAc) blocks stress-regulated changes in ethanol drinking including kappa-opioid receptor-stimulated potentiation of alcohol drinking, demonstrating that NAc G9a is specifically required for stress-regulated (not baseline) alcohol drinking behavior. Viral-mediated G9a knockdown in NAc, chronic intermittent ethanol (CIE) mouse model, pharmacological G9a inhibition Addiction biology Medium 34013595
2014 G9a-mediated H3K9me2 in naive T cells restricts Th17 and Treg differentiation by limiting chromatin accessibility and TGF-β1 responsiveness; H3K9me2 is lost upon T cell activation, and G9a loss increases chromatin accessibility and TGF-β1 sensitivity to promote Th17/Treg differentiation. T cell-specific G9a KO mice, T cell transfer colitis model, in vitro differentiation assays, ChIP for H3K9me2, ATAC-seq/chromatin accessibility The Journal of clinical investigation High 24667637

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 H3K9 methyltransferase G9a and the related molecule GLP. Genes & development 460 21498567
2006 Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes & development 419 17085482
2008 G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. The EMBO journal 319 18818694
2015 Functional Role of G9a Histone Methyltransferase in Cancer. Frontiers in immunology 201 26441991
2012 Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. The EMBO journal 164 23178591
2009 Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins. The Journal of biological chemistry 164 19144645
2019 Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nature medicine 157 31270502
2008 G9a and HP1 couple histone and DNA methylation to TNFalpha transcription silencing during endotoxin tolerance. The Journal of biological chemistry 141 18809684
2013 BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy 129 24322755
2017 G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 113 28630300
2019 FOXO1 degradation via G9a-mediated methylation promotes cell proliferation in colon cancer. Nucleic acids research 107 30535125
2008 Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. The Journal of biological chemistry 106 19001366
2010 LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome research 100 21149390
2015 EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 91 26320100
2017 Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy. Circulation 90 28778944
2019 Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents. European journal of medicinal chemistry 86 31276898
2010 Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D. Epigenetics & chromatin 85 20334638
2019 CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. JCI insight 82 31095524
2019 Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma. Clinical epigenetics 82 31775874
2014 Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. The Journal of clinical investigation 78 24667637
2012 Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A. Proceedings of the National Academy of Sciences of the United States of America 75 23112189
2019 CNTN5-or EHMT2-human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks. eLife 73 30747104
2017 G9a coordinates with the RPA complex to promote DNA damage repair and cell survival. Proceedings of the National Academy of Sciences of the United States of America 70 28698370
2016 Alternative Splicing of G9a Regulates Neuronal Differentiation. Cell reports 70 26997278
2021 Downregulation of a Dorsal Root Ganglion-Specifically Enriched Long Noncoding RNA is Required for Neuropathic Pain by Negatively Regulating RALY-Triggered Ehmt2 Expression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 67 34383386
2018 Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway. Cell death & disease 67 29374157
2017 The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function. Frontiers in immunology 67 28443098
2022 EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms. The FEBS journal 60 34954891
2015 EHMT2 directs DNA methylation for efficient gene silencing in mouse embryos. Genome research 59 26576615
2017 Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase. Journal of medicinal chemistry 58 28135087
2022 An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer. Molecular cancer 57 35477569
2020 Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis. Cancer discovery 57 32269030
2015 Down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation. Oncotarget 56 25595900
2020 G9a Plays Distinct Roles in Maintaining DNA Methylation, Retrotransposon Silencing, and Chromatin Looping. Cell reports 51 33113380
2019 G9a and histone deacetylases are crucial for Snail2-mediated E-cadherin repression and metastasis in hepatocellular carcinoma. Cancer science 51 31432592
2018 Interplay between EZH2 and G9a Regulates CXCL10 Gene Repression in Idiopathic Pulmonary Fibrosis. American journal of respiratory cell and molecular biology 51 29053336
2016 G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells. Cell reports 51 27052169
2016 Human EHMT2/G9a activates p53 through methylation-independent mechanism. Oncogene 49 27452519
2016 Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB. Oncotarget 47 27174920
2021 Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma. Hepatology (Baltimore, Md.) 46 33222246
2013 Histone-lysine methyltransferase EHMT2 is involved in proliferation, apoptosis, cell invasion, and DNA methylation of human neuroblastoma cells. Anti-cancer drugs 46 23466651
2019 G9a promotes cell proliferation and suppresses autophagy in gastric cancer by directly activating mTOR. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 31647887
2021 Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a. Life (Basel, Switzerland) 41 34685453
2021 SPOP mutation induces DNA methylation via stabilizing GLP/G9a. Nature communications 40 34588438
2016 G9a promotes proliferation and inhibits cell cycle exit during myogenic differentiation. Nucleic acids research 40 27229136
2015 G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation. Scientific reports 40 26688070
2020 EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation. International journal of biological sciences 39 32174799
2017 Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1. Biochimica et biophysica acta. Molecular basis of disease 38 29101051
2001 Novel NG36/G9a gene products encoded within the human and mouse MHC class III regions. Mammalian genome : official journal of the International Mammalian Genome Society 38 11707778
2020 Targeting EHMT2/ G9a for cancer therapy: Progress and perspective. European journal of pharmacology 37 33347828
2022 Discovery of the First-in-Class G9a/GLP Covalent Inhibitors. Journal of medicinal chemistry 35 35763668
2021 G9a Inhibition Enhances Checkpoint Inhibitor Blockade Response in Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 35 33589432
2015 Regulation of cell differentiation and function by the euchromatin histone methyltranserfases G9a and GLP. Biochemistry and cell biology = Biochimie et biologie cellulaire 35 26198080
2023 Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer. Gastroenterology 34 38065340
2018 G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst. eLife 34 29745895
2022 PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing. Molecular cell 33 36476474
2021 Emerging role of G9a in cancer stemness and promises as a therapeutic target. Oncogenesis 33 34775469
2012 Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a. Cell stem cell 33 22704517
2021 G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor-mediated cell death. Blood advances 31 33938943
2017 Methyltransferase G9a promotes cervical cancer angiogenesis and decreases patient survival. Oncotarget 31 28977928
2017 Protein-lysine methyltransferases G9a and GLP1 promote responses to DNA damage. Scientific reports 31 29192276
2020 EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway. International journal of molecular sciences 29 32028644
2020 G9a Promotes Breast Cancer Recurrence through Repression of a Pro-inflammatory Program. Cell reports 29 33147463
2019 EHMT2 and SETDB1 protect the maternal pronucleus from 5mC oxidation. Proceedings of the National Academy of Sciences of the United States of America 29 31088968
2023 G9a promotes immune suppression by targeting the Fbxw7/Notch pathway in glioma stem cells. CNS neuroscience & therapeutics 28 36971192
2017 Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorganic & medicinal chemistry 28 28662962
2019 Insights for the design of protein lysine methyltransferase G9a inhibitors. Future medicinal chemistry 27 31141392
2018 EHMT2 is a metastasis regulator in breast cancer. Biochemical and biophysical research communications 27 29337058
2016 The lysine methyltransferase Ehmt2/G9a is dispensable for skeletal muscle development and regeneration. Skeletal muscle 27 27239264
2019 Cyclin D1 integrates G9a-mediated histone methylation. Oncogene 26 30718920
2017 KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels. Scientific reports 26 28327608
2017 G9a controls placental vascular maturation by activating the Notch Pathway. Development (Cambridge, England) 26 28455378
2016 G9a inhibition induced PKM2 regulates autophagic responses. The international journal of biochemistry & cell biology 26 27417236
2022 G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation. Gastroenterology 25 36272457
2023 ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers. Nature cell biology 24 36604593
2017 G9a - An Appealing Antineoplastic Target. Current cancer drug targets 24 27174055
2021 Heterodimerization of H3K9 histone methyltransferases G9a and GLP activates methyl reading and writing capabilities. The Journal of biological chemistry 23 34619147
2017 The expanding role of the Ehmt2/G9a complex in neurodevelopment. Neurogenesis (Austin, Tex.) 22 28596979
2020 EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma. eLife 21 33252038
2016 Depletion of G9a gene induces cell apoptosis in human gastric carcinoma. Oncology reports 21 27081761
2021 Histone Methyltransferases SUV39H1 and G9a and DNA Methyltransferase DNMT1 in Penumbra Neurons and Astrocytes after Photothrombotic Stroke. International journal of molecular sciences 19 34830365
2020 Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance. Frontiers in genetics 19 33088284
2020 The Histone Methyltransferase Gene G9A Is Regulated by Nuclear Receptor 4A1 in Alveolar Rhabdomyosarcoma Cells. Molecular cancer therapeutics 19 33277444
2017 Essential roles of G9a in cell proliferation and differentiation during tooth development. Experimental cell research 18 28527696
2017 Methyltransferase G9A Regulates Osteogenesis via Twist Gene Repression. Journal of dental research 18 28644763
2023 HMGB1 neuroimmune signaling and REST-G9a gene repression contribute to ethanol-induced reversible suppression of the cholinergic neuron phenotype. Molecular psychiatry 17 37402853
2022 Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis. Cancer research 17 35149587
2021 EHMT2 promotes the pathogenesis of hepatocellular carcinoma by epigenetically silencing APC expression. Cell & bioscience 17 34344448
2024 G9a Inhibition Promotes Neuroprotection through GMFB Regulation in Alzheimer's Disease. Aging and disease 16 37307824
2024 EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer. Proceedings of the National Academy of Sciences of the United States of America 16 38814866
2023 Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Molecular oncology 16 36896891
2022 Calreticulin enhances gastric cancer metastasis by dimethylating H3K9 in the E-cadherin promoter region mediating by G9a. Oncogenesis 16 35641480
2019 Inhibition of Histone Methyltransferase G9a Attenuates Noise-Induced Cochlear Synaptopathy and Hearing Loss. Journal of the Association for Research in Otolaryngology : JARO 16 30710318
2025 Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 15 39810240
2021 EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors. International journal of molecular sciences 15 34681949
2019 SUMOylation of G9a regulates its function as an activator of myoblast proliferation. Cell death & disease 15 30867409
2024 Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma. Hepatology communications 14 38285887
2022 Cholinergic REST-G9a gene repression through HMGB1-TLR4 neuroimmune signaling regulates basal forebrain cholinergic neuron phenotype. Frontiers in molecular neuroscience 14 36072299
2021 The histone methyltransferase G9a mediates stress-regulated alcohol drinking. Addiction biology 14 34013595
2021 H3K9 methyltransferase EHMT2/G9a controls ERVK-driven noncanonical imprinted genes. Epigenomics 13 34519223

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