Affinage

EHMT2

Histone-lysine N-methyltransferase EHMT2 · UniProt Q96KQ7

Length
1210 aa
Mass
132.4 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 48 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EHMT2 (G9a) is a SET-domain histone lysine methyltransferase that, as an obligate heterodimer with GLP/EHMT1, catalyzes the majority of euchromatic H3K9 mono- and dimethylation to establish transcriptional silencing across diverse developmental and somatic contexts (PMID:21498567, PMID:34619147). Heterodimerization with GLP relieves autoinhibition and enhances nucleosomal methyltransferase activity approximately ten-fold; G9a further automethylates itself at K239 to generate an HP1-binding platform that links H3K9me2 deposition to heterochromatin reader recruitment (PMID:34619147, PMID:17962312). Beyond histones, G9a methylates non-histone substrates including FOXO1 (promoting SKP2-dependent degradation) and MDC1 (facilitating ATM spreading at DNA damage sites), and recruits DNA methyltransferases to target loci through a catalytic-activity-independent scaffolding function that maintains DNA methylation at imprinted and germline-gene promoters (PMID:30535125, PMID:30022091, PMID:27052169, PMID:18818694). G9a also operates as a methyltransferase-independent transcriptional co-activator by associating with E2F1/PCAF and p300/CBP complexes to promote histone acetylation at select gene promoters (PMID:27229136, PMID:27452519).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 High

    Demonstrating that G9a automethylates K239 to create an HP1-binding motif established that the enzyme generates its own reader-binding site, directly coupling H3K9 methyltransferase activity to heterochromatin effector recruitment.

    Evidence In vitro methyltransferase assay with K239A mutagenesis and GFP co-localization in COS-7 cells

    PMID:17962312

    Open questions at the time
    • Structural basis of K239me-HP1 interaction not resolved
    • In vivo stoichiometry of automethylation unknown
  2. 2008 High

    Two independent studies established that G9a mediates euchromatic gene silencing through both H3K9 methylation-dependent and -independent mechanisms: the Air ncRNA targets G9a to chromatin for locus-specific silencing, while catalytically inactive G9a/GLP retains the ability to direct DNA methylation, revealing separable enzymatic and scaffolding repressive functions.

    Evidence RNA immunoprecipitation and allele-specific expression in G9a KO mouse placenta; catalytic mutant knock-in ES cells with bisulfite sequencing

    PMID:18818694 PMID:18988810

    Open questions at the time
    • How G9a scaffolding recruits DNMTs at the molecular level was not defined
    • Breadth of ncRNA-directed G9a targeting beyond Air unknown
  3. 2010 High

    Identification of linker histone H1.2 K187 as a G9a/GLP substrate and demonstration that chromatin remodeler LSH cooperates with G9a for developmental DNA methylation expanded the enzyme's substrate repertoire and upstream regulatory network.

    Evidence In vitro methylation with mass spectrometry site mapping; LSH KO MEFs with genome-wide methylation profiling and ChIP

    PMID:20334638 PMID:21149390

    Open questions at the time
    • Functional consequence of H1.2K187 methylation on chromatin compaction unclear
    • Whether LSH directly contacts G9a or acts indirectly not resolved
  4. 2011 High

    Biochemical demonstration that G9a and GLP exist predominantly as a heteromeric complex responsible for the bulk of euchromatic H3K9me1/me2 established the heterodimer as the physiologically relevant enzymatic unit.

    Evidence Biochemical fractionation, co-immunoprecipitation, and enzymatic assays

    PMID:21498567

    Open questions at the time
    • Quantitative contribution of homodimers in specific tissues not determined
    • Regulation of heterodimer versus homodimer ratio unknown
  5. 2012 High

    PKA-mediated induction of G9a expression linked extracellular signaling to epigenetic silencing of pluripotency genes (Oct3/4, Nanog), establishing G9a as a signal-responsive effector of ESC differentiation.

    Evidence PKA activation in G9a KO mouse ESCs with ChIP and bisulfite sequencing

    PMID:22704517

    Open questions at the time
    • Direct phosphorylation of G9a by PKA not demonstrated
    • Kinetics of G9a protein stabilization versus transcriptional upregulation not distinguished
  6. 2015 High

    Genome-wide studies in multiple contexts—embryonic DNA methylation of germline genes, PPARγ locus repression in preadipocytes, γ-globin silencing in erythroid cells, and PRC2 pathway cross-talk in cancer—revealed G9a as a versatile epigenetic gatekeeper controlling lineage-specific gene programs and chromatin accessibility.

    Evidence Ehmt2 KO mice with WGBS; genome-wide H3K9me2 profiling in adipose KO; CRISPR/shRNA/UNC0638 in primary erythroid cells with ChIP-seq; ChIP and epistasis in pancreatic cancer cells

    PMID:23178591 PMID:26320100 PMID:26576615 PMID:26688070

    Open questions at the time
    • How G9a target selection differs across lineages not systematically resolved
    • Relative contribution of H3K9me2 versus DNA methylation at individual loci varies and is incompletely understood
  7. 2016 High

    Discovery that G9a functions as both a co-repressor (via H3K9me2-dependent silencing of p21/Rb1) and a co-activator (via methyltransferase-independent association with E2F1/PCAF and p300/CBP complexes) resolved the paradox of G9a promoting gene activation at some loci, and alternative splicing of exon 10 was shown to regulate nuclear accumulation during neuronal differentiation.

    Evidence G9a KD transcriptome, ChIP, and Co-IP of E2F1/PCAF in skeletal muscle cells; Co-IP of hG9a-p300/CBP with ChIP at Puma promoter; splicing reporter and subcellular fractionation in N2a cells; catalytic mutant ES cells with DNMT recruitment assays at ICRs

    PMID:26997278 PMID:27052169 PMID:27229136 PMID:27452519

    Open questions at the time
    • How G9a switches between co-activator and co-repressor modes at individual promoters remains unclear
    • Structural basis of the E2F1/PCAF-G9a interaction not determined
    • Exon 10 splicing regulators not fully identified
  8. 2017 High

    Tissue-specific conditional knockouts revealed essential G9a roles in cardiomyocyte homeostasis (via an EZH2/MEF2C co-repressor complex), placental vascular development (via Notch pathway activation), and cranial neural crest osteogenesis (via Twist1/2 repression), demonstrating context-dependent partnering with distinct transcription factors.

    Evidence Cardiac-specific G9a KO with ChIP-seq and Co-IP; endothelial progenitor G9a KO with Notch genetic rescue; Wnt1-Cre neural crest G9a KO with ChIP at Twist loci

    PMID:28455378 PMID:28644763 PMID:28778944

    Open questions at the time
    • Whether the G9a-EZH2-MEF2C complex exists outside cardiomyocytes not tested
    • Direct versus indirect Notch activation by G9a unresolved
  9. 2018 High

    Identification of MDC1-K45 as an EHMT2 substrate that promotes MDC1-ATM interaction at DNA damage sites extended G9a function to the DNA damage response, while maternal G9a depletion in oocytes revealed its role in gene regulatory network timing during preimplantation development.

    Evidence In vitro methylation assay, Co-IP, and ChIP at DSB sites with ATM inhibition; maternal G9a KO with single-cell RNA-seq in preimplantation embryos

    PMID:29745895 PMID:30022091

    Open questions at the time
    • Reader of MDC1-K45me not identified
    • Whether G9a-mediated DDR methylation is catalyzed by heterodimer or homodimer unknown
  10. 2019 High

    Multiple studies converged to show G9a methylates the non-histone substrate FOXO1 (K273) to trigger SKP2-dependent degradation, physically interacts with EZH2 for interdependent H3K9/H3K27 methylation, cooperates with HP1α to repress PGC1α in fibrosis, and modulates T cell fate by restricting chromatin accessibility at TGF-β1-responsive loci.

    Evidence In vitro methylation with K273 mutagenesis and protein stability assays; proximity ligation assay and Re-ChIP in IPF fibroblasts; ChIP and bleomycin model; conditional G9a KO in naive CD4+ T cells with ATAC-seq

    PMID:24667637 PMID:29053336 PMID:30535125 PMID:31095524

    Open questions at the time
    • Full spectrum of non-histone G9a substrates not catalogued
    • Structural basis of G9a-EZH2 interaction not resolved
    • How G9a is recruited to fibrotic versus immune target loci differentially is unclear
  11. 2020 High

    Genome-wide dissection using catalytic mutant and G9a-depleted ES cells showed that G9a controls chromatin looping and retrotransposon silencing through both catalytic and non-catalytic mechanisms, including regulation of CTCF/cohesin binding, while in cancer G9a gain-of-function mutations drive WNT/β-catenin activation via DKK1 repression.

    Evidence WGBS, ATAC-seq, ChIP-seq, Hi-C in G9a mutant ES cells; gain-of-function mutation analysis with ChIP at DKK1 in melanoma models

    PMID:32269030 PMID:33113380

    Open questions at the time
    • How G9a non-catalytically influences CTCF binding mechanistically is unknown
    • Whether DKK1 repression is the principal oncogenic output of G9a across cancer types not established
  12. 2021 High

    Quantitative reconstitution of defined homo- and heterodimers demonstrated that G9a-GLP heterodimerization relieves autoinhibition and enhances nucleosomal H3K9me2 catalysis ~10-fold, while SPOP-mediated polyubiquitination of GLP was identified as a regulatory mechanism controlling G9a complex stability and downstream DNA methylation.

    Evidence Recombinant defined dimers with kinetic assays and cross-linking MS; SPOP ubiquitination assays with genome-wide methylome in prostate cancer

    PMID:34588438 PMID:34619147

    Open questions at the time
    • Structural model of full heterodimer on nucleosome not available
    • Whether SPOP also directly ubiquitinates G9a not tested
  13. 2022 High

    Discovery of PALI1 as a bridge forming a G9A-PALI1-PRC2 super-complex for dual H3K9/K27 methylation at developmental genes, covalent inhibitors targeting a cysteine in G9a's substrate-binding site, and HECTD2-mediated G9a degradation expanded both mechanistic understanding and pharmacological toolkits.

    Evidence Co-IP and ChIP-seq for PALI1-PRC2 in prostate cancer; X-ray crystallography of covalent inhibitor-G9a complex; HECTD2 overexpression with ChIP at TNFAIP1 promoter

    PMID:34972816 PMID:35763668 PMID:36476474

    Open questions at the time
    • PALI1 structural interface with G9a not resolved
    • In vivo pharmacokinetics and selectivity of covalent inhibitors not reported
    • HECTD2 regulation of G9a not confirmed in non-gut tissues
  14. 2023 High

    Identification of sequence-specific recruiters (ZFP462 at transposable element-derived enhancers, CHD4 at the galectin-7 locus) and tissue-specific targets (Ces1 in renal tubules, Fbxw7 in glioma) showed how G9a achieves locus-selective silencing through combinatorial partnerships with zinc-finger proteins, chromatin remodelers, and tissue-restricted transcription factors.

    Evidence ChIP-seq/ATAC-seq in ZFP462 KO ESCs; CRISPR screen and Co-IP of CHD4-EHMT2; renal tubular G9a KO with ChIP at Ces1; ChIP at Fbxw7 in glioma

    PMID:36604593 PMID:36971192 PMID:37042626 PMID:38065340

    Open questions at the time
    • Comprehensive catalogue of zinc-finger recruiters for G9a/GLP not available
    • Whether CHD4-EHMT2 complex requires CHD4 ATPase activity unknown
    • Mechanisms distinguishing G9a activator versus repressor targeting at different loci remain incompletely understood

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of the full-length G9a-GLP heterodimer on nucleosomes, the complete non-histone substrate repertoire, the molecular logic determining whether G9a acts as a co-repressor or co-activator at a given locus, and the therapeutic window of G9a inhibitors in vivo.
  • No full-length heterodimer cryo-EM or crystal structure on nucleosome
  • Systematic unbiased identification of non-histone substrates not performed
  • Co-activator switching mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0042393 histone binding 4 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-1266738 Developmental Biology 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
CBX5CCND1CHD4EHMT1EZH2HOXA9PALI1ZFP462
Complex memberships
CHD4-EHMT2 complexG9A-PALI1-PRC2 super-complexG9a-EZH2-MEF2C complexG9a/GLP heterodimer

Evidence

Reading pass · 48 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 The Air noncoding RNA targets G9a (EHMT2) to chromatin at the Slc22a3 promoter in placenta, where G9a mediates localized H3K9 methylation and transcriptional repression; genetic ablation of G9a results in biallelic transcription of Slc22a3, establishing G9a as the effector of ncRNA-directed epigenetic silencing. RNA immunoprecipitation, ChIP, genetic knockout in mouse, allele-specific expression analysis Science High 18988810
2011 G9a and GLP exist predominantly as a G9a-GLP heteromeric complex that is the primary enzyme for H3K9me1 and H3K9me2 in mammalian euchromatin. Biochemical fractionation, co-immunoprecipitation, enzymatic assays Genes & development High 21498567
2008 G9a/GLP independently mediates both H3K9 methylation and DNA methylation to silence transcription; ES cells expressing catalytically inactive G9a/GLP maintain DNA methylation at target gene promoters and gene silencing, but G9a/GLP KO leads to loss of DNA methylation and gene re-expression, demonstrating two separable repressive mechanisms. Catalytic mutant knock-in ES cells, bisulfite sequencing, DNMT inhibitor rescue, gene expression analysis The EMBO journal High 18818694
2007 G9a automethylates itself at K239 (ARKT motif), creating a binding site for HP1 proteins (HP1α and HP1γ); mutation of K239A abolishes HP1 co-localization in COS-7 cells. G9a also methylates non-histone proteins bearing ARKS/T motifs. In vitro methyltransferase assay, site-directed mutagenesis (K239A), co-immunoprecipitation, GFP co-localization in COS-7 cells Nucleic acids research High 17962312
2010 G9a/KMT1C and GLP/KMT1D methylate linker histone H1.2 at K187 in the C-terminus in vitro and in vivo; this is a variant-specific mark distinct from H1.4K26 methylation, and unlike H1.4K26me, H1.2K187me cannot recruit HP1 and is not reversed by JMJD2D. In vitro methyltransferase assay, mass spectrometry, chromatin fractionation, in vivo modification mapping Epigenetics & chromatin High 20334638
2010 LSH (chromatin remodeling ATPase) cooperates with the G9a/GLP complex for developmentally programmed DNA methylation; loss of LSH compromises G9a recruitment to specific loci, linking chromatin remodeling to G9a-dependent epigenetic silencing. Genome-wide DNA methylation profiling, ChIP, genetic knockout in mouse embryonic fibroblasts Genome research High 21149390
2012 PKA activation increases G9a protein expression, leading to H3K9 dimethylation and DNA methylation at Oct3/4 and Nanog promoters and accelerated ESC differentiation; G9a deletion abolishes PKA-elicited epigenetic modification and differentiation acceleration. PKA activation, G9a KO mouse ESCs, ChIP, bisulfite sequencing, developmental timing assays Cell stem cell High 22704517
2014 G9a interacts with the leukemogenic transcription factor HoxA9 and its methyltransferase activity is required for HoxA9-dependent transcription; loss of G9a delays AML progression and reduces leukemia stem cell frequency in mouse models. Co-immunoprecipitation, conditional KO mouse AML models, leukemia stem cell frequency assays, pharmacological inhibition Genes & development High 24532712
2014 G9a-mediated H3K9me2 in naive CD4+ T cells restricts Th17 and Treg differentiation by limiting chromatin accessibility and TGF-β1 responsiveness; H3K9me2 is lost upon T cell activation, and G9a-deficient naive T cells show increased sensitivity to TGF-β1. T cell transfer colitis model, G9a conditional KO, ATAC-seq/chromatin accessibility, in vitro differentiation assays The Journal of clinical investigation High 24667637
2015 EHMT2 directs DNA methylation at CpG-rich promoters of germline-specific genes and at the Slc38a4 imprinted locus in mouse embryogenesis; DNA methylation is instrumental for EHMT2-mediated gene silencing at these loci. Ehmt2 knockout mice, genome-wide bisulfite sequencing, ChIP, gene expression analysis during embryogenesis Genome research High 26576615
2015 EHMT1 and EHMT2 are epigenetic repressors of the γ-globin gene; inhibition or shRNA knockdown of EHMT1/2 reduces H3K9me2 at the γ-globin locus, increases H3K9Ac, and induces fetal hemoglobin expression in primary human adult erythroid cells. Small molecule inhibitor (UNC0638), shRNA knockdown, CRISPR/Cas9 KO, ChIP-seq, RNA-seq in primary human erythroid cells Blood High 26320100
2016 G9a promotes neuronal differentiation via alternative splicing: inclusion of exon 10 (E10) increases G9a nuclear localization and global H3K9me2 without affecting catalytic activity; the E10+ isoform regulates its own pre-mRNA splicing creating a positive feedback loop. Alternative splicing analysis, N2a neuronal differentiation model, subcellular fractionation, H3K9me2 quantification, splicing reporter assays Cell reports Medium 26997278
2016 G9a functions as both a co-repressor and co-activator in skeletal muscle cells: it blocks cell cycle exit via methylation-dependent repression of p21 and Rb1 (MyoD target genes), and activates E2F1-target genes by associating with the E2F1/PCAF complex in a methyltransferase-independent manner enhancing PCAF occupancy and histone acetylation. G9a knockdown, transcriptome analysis, ChIP, co-immunoprecipitation (E2F1/PCAF complex), cell cycle analysis Nucleic acids research High 27229136
2016 G9a/GLP complex is required for stable maintenance of imprinted DNA methylation at ICRs in embryonic stem cells through a catalytic-activity-independent mechanism; G9a/GLP recruit de novo DNA methyltransferases to antagonize TET dioxygenase-dependent erosion of DNA methylation at ICRs. G9a/GLP KO and catalytic mutant ES cells, bisulfite sequencing, DNMT recruitment assays Cell reports High 27052169
2017 G9a is required for cardiomyocyte homeostasis by mediating H3K9 dimethylation-dependent repression of key cardiomyocyte function genes; G9a forms a complex with EZH2 and MEF2C to maintain heterochromatin and repress developmental genes, and promotes cardiac hypertrophy by repressing antihypertrophic genes. Cardiac-specific conditional G9a KO mouse, ChIP-seq, RNA-seq, co-immunoprecipitation Circulation High 28778944
2017 G9a activates the Notch pathway (including Rbpj) to promote placental vascular maturation; G9a deficiency in endothelial progenitors reduces endothelial proliferation, and Notch pathway activation rescues placental vascular expansion in G9a-deficient embryos. Conditional G9a KO in endothelial progenitors, genetic Notch rescue, vascular phenotype analysis, gene expression profiling Development High 28455378
2019 FOXO1 is methylated by G9a at K273 in vitro and in vivo; this methylation increases FOXO1 interaction with the E3 ligase SKP2 leading to FOXO1 protein degradation and increased colon cancer cell proliferation. Insulin induces G9a expression to promote FOXO1 degradation via K273 methylation. In vitro methyltransferase assay, co-immunoprecipitation, protein stability assay, site-directed mutagenesis (K273), FACS apoptosis Nucleic acids research High 30535125
2019 EHMT2 contributes to PTEN transcriptional repression via H3K9 methylation, facilitating AKT pathway activation; genetic or pharmacological EHMT2 inhibition de-represses PTEN and enhances EGFR-TKI sensitivity in resistant NSCLC cells. EHMT2 inhibitor (UNC0638), siRNA knockdown, ChIP, cell viability, migration, tumor sphere assays Cell death & disease Medium 29374157
2019 G9a suppresses autophagy in gastric cancer cells by activating mTOR transcription via H3K9 monomethylation at the mTOR promoter; G9a knockdown reduces H3K9me1 at the mTOR promoter and decreases mTOR expression, and mTOR activation partially rescues G9a KD phenotypes. G9a siRNA knockdown, BIX01294 inhibitor, ChIP at mTOR promoter, cell proliferation and autophagy assays, xenograft model FASEB journal Medium 31647887
2019 G9a and EZH2 physically interact in IPF fibroblasts and interdependently regulate CXCL10 promoter methylation: EZH2 knockdown reduces both H3K27me3 and G9a/H3K9me3, while G9a knockdown reduces EZH2 and H3K27me3, revealing a functionally interdependent epigenetic repressor complex. ChIP, Re-ChIP, proximity ligation assay, siRNA knockdown in IPF fibroblasts American journal of respiratory cell and molecular biology High 29053336
2019 The CBX5 (HP1α)/G9a pathway is essential for fibroblast activation in pulmonary fibrosis by epigenetically repressing PPARGC1A (PGC1α); both TGFβ and increased matrix stiffness activate this pathway, and inhibition of CBX5/G9a elevates PGC1α and reduces lung collagen accumulation. ChIP, G9a/CBX5 inhibition, bleomycin injury model, TGFβ and stiffness treatments in lung fibroblasts JCI insight High 31095524
2015 G9a represses PPARγ expression in preadipocytes via H3K9me2 at the entire PPARγ locus; G9a deletion removes H3K9me2, increases chromatin accessibility and C/EBPβ binding to the PPARγ promoter, promoting adipogenesis. G9a also facilitates Wnt10a expression independently of its enzymatic activity. G9a KO mouse, genome-wide H3K9me2 profiling, ChIP, chromatin accessibility assays, in vivo adipose tissue deletion The EMBO journal High 23178591
2018 MDC1 is methylated at lysine 45 dominantly by EHMT2; MDC1 interacts preferentially with EHMT1, interaction that is facilitated by ATM signaling after DNA damage; EHMT2-mediated MDC1-K45 methylation promotes MDC1-ATM interaction to expand activated ATM at DNA damage sites. Co-immunoprecipitation, in vitro methylation assay, ChIP at DSB sites, ATM inhibition, EHMT1/2 knockdown Scientific reports High 30022091
2020 G9a plays distinct roles in maintaining DNA methylation, retrotransposon silencing, and chromatin looping; both catalytic-dependent and -independent mechanisms control chromatin accessibility and transcription; loss of G9a leads to aberrant CTCF and cohesin binding and differential chromatin looping at retrotransposons. G9a depletion and catalytic mutant ES cells, WGBS, ATAC-seq, ChIP-seq, Hi-C Cell reports High 33113380
2021 Heterodimerization of G9a and GLP significantly enhances both H3K9me2 reading and writing activities; the G9a-GLP heterodimer shows ~10-fold higher turnover on nucleosomal substrates compared to homodimers, suggesting heterodimerization relieves autoinhibition of the homodimers. Recombinant production of defined homo- and heterodimers, in vitro methyltransferase assay on peptides and nucleosomes, cross-linking mass spectrometry The Journal of biological chemistry High 34619147
2021 SPOP E3 ligase promotes polyubiquitination and degradation of GLP; SPOP mutation stabilizes GLP and its partner G9a, causing global DNA hypermethylation including silencing of tumor suppressor genes (FOXO3, GATA5, NDRG1) in prostate cancer. Co-immunoprecipitation, ubiquitination assay, genome-wide DNA methylome analysis, SPOP mutant cell lines and primary specimens Nature communications High 34588438
2015 G9a orchestrates H3K27 methylation indirectly by upregulating PCL3 (increasing PRC2 recruitment to E-cadherin promoter) and downregulating the H3K27 demethylase KDM7A; this mechanism represses E-cadherin and induces EMT in pancreatic cancer cells. ChIP, G9a overexpression/knockdown, PCL3 and KDM7A manipulation, gene expression analysis in PANC-1 cells Scientific reports Medium 26688070
2016 Human G9a (hG9a) activates p53 transcriptional activity through a methylation-independent mechanism; hG9a interacts with histone acetyltransferase p300/CBP, resulting in increased histone acetylation at pro-apoptotic gene (Puma) promoters and enhanced apoptosis. Co-immunoprecipitation (hG9a-p300/CBP), ChIP (histone acetylation at Puma promoter), p53 transcription reporter, shRNA knockdown Oncogene Medium 27452519
2016 G9a inhibits nerve injury-induced expression of mu, kappa, and delta opioid receptors in dorsal root ganglia by increasing H3K9me2 at opioid receptor gene promoters; mechanistically, increased G9a/H3K9me2 binding blocks CREB access to the Oprm1 promoter. ChIP at opioid receptor gene promoters, G9a inhibitor injection, shRNA knockdown, behavioral pain assays Molecular pain Medium 27927796
2019 Snail2 interacts with G9a and HDACs to form a transcriptional repressor complex that suppresses E-cadherin transcription via H3K9 methylation at the E-cadherin promoter, driving EMT and metastasis in HCC. Co-immunoprecipitation (Snail2-G9a-HDAC), ChIP at E-cadherin promoter, G9a/HDAC inhibitor rescue, migration/invasion assays, mouse metastasis model Cancer science Medium 31432592
2019 Cyclin D1 directly associates with G9a and is required for G9a recruitment to target genes in chromatin; cyclin D1 is necessary for G9a-mediated H3K9me2 of histones and for nuclear lamina-LAD interactions. Co-immunoprecipitation, ChIP at target genes, cyclin D1 KO cells, Hi-C/LAD analysis Oncogene Medium 30718920
2023 ZFP462 recruits the G9a/GLP complex to transposable element-derived enhancers bearing pluripotency and meso-endoderm transcription factor binding sites, seeding heterochromatin to restrict TF binding and silence meso-endodermal genes during neural lineage specification of ESCs. Protein interaction screen, ChIP-seq, ATAC-seq, ZFP462 KO ESCs, gene expression analysis Nature cell biology High 36604593
2022 PALI1 interacts with G9A to bridge 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 of developmental regulators in prostate cancer. Co-immunoprecipitation, ChIP-seq, G9A/EZH2 pharmacological inhibition, in vitro and in vivo tumor models Molecular cell High 36476474
2023 CHD4 recruits EHMT2 to form a co-transcriptional silencing complex at the galectin-7 locus; EHMT2 inhibition disrupts this complex, upregulates galectin-7, and converts immunosuppressive MSS colorectal tumors to a T-cell-inflamed phenotype. CRISPR screen, ChIP (CHD4-EHMT2 co-occupancy), co-immunoprecipitation, coculture immunogenicity assays Gastroenterology Medium 38065340
2023 G9a suppresses transcription of the lipolytic enzyme Ces1 by H3K9 methylation at its promoter; G9a and FXR competitively bind the same Ces1 promoter regions; renal tubular G9a knockout reduces lipid accumulation and alleviates acute kidney injury. Renal tubular specific G9a KO mouse (Ehmt2Ksp), ChIP at Ces1 promoter, competitive binding assay, lipid accumulation quantification, I/R injury model EMBO reports High 37042626
2024 EHMT2 increases H3K9me2 methylation at the SFRP1 promoter, reducing SFRP1 expression and thereby activating the WNT/β-catenin pathway to drive neuroendocrine transformation and erlotinib resistance in NSCLC. ChIP at SFRP1 promoter, EHMT2 inhibitor treatment, NE transformation cell lines and CDX mice, clinical sample validation PNAS Medium 38814866
2018 G9a regulates preimplantation development by accumulating at the 4-to-8 cell stage to promote timely repression of 4-cell-stage-specific genes; loss of maternally inherited G9a disrupts gene regulatory networks, causes developmental delay, and destabilizes ICM lineages. Maternal G9a depletion in oocytes, single-cell RNA-seq, immunofluorescence, blastocyst phenotype analysis eLife High 29745895
2020 EHMT2 suppresses canonical Wnt signaling in embryonal rhabdomyosarcoma by activating expression of the Wnt antagonist DKK1; mechanistically, EHMT2 impacts Sp1 and p300 enrichment at the DKK1 promoter; EHMT2 inhibition reduces DKK1 and elevates Wnt signaling to promote myogenic differentiation. EHMT2 siRNA/inhibitor, ChIP (Sp1, p300, H3K9me2 at DKK1 promoter), Wnt reporter, xenograft model, recombinant DKK1 rescue eLife High 33252038
2020 Recurrent activating mutations and copy gains in G9a drive melanoma tumor growth and an immunologically cold microenvironment by suppressing the WNT antagonist DKK1 via H3K9 methylation, activating WNT/β-catenin signaling. Gain-of-function mutation analysis, G9a inhibition in vitro and in vivo, ChIP at DKK1 locus, tumor immune microenvironment profiling Cancer discovery High 32269030
2022 Discovery of the first covalent G9a/GLP inhibitors targeting a cysteine residue at the substrate binding site; X-ray crystallography confirms covalent binding mode; covalent inhibitor shows improved potency over non-covalent UNC0642 and kinetic preference for G9a over GLP. X-ray crystallography, mass spectrometry-based covalent engagement assay, in vitro enzymatic assay, cellular H3K9me2 reduction Journal of medicinal chemistry High 35763668
2015 EHMT2 binds the SIAH1 gene promoter and represses its transcription via H3K9 methylation, thereby supporting cancer cell proliferation; EHMT2 inhibitor BIX-01294 suppresses cancer cell growth. ChIP at SIAH1 promoter, siRNA knockdown, cell growth assays Neoplasia Medium 21847359
2017 G9a regulates HMGA1 expression via H3K9 methylation, and HMGA1 controls insulin receptor (INSR) gene transcription; G9a knockdown reduces insulin receptor levels and impairs insulin signaling, while G9a overexpression prevents palmitate-induced insulin resistance. G9a knockdown/overexpression in hepatic cells, db/db and HFD mouse models, HMGA1 rescue experiment, ChIP Biochimica et biophysica acta Medium 29101051
2023 EHMT2 regulates expression of EHMT2/G9a itself via RALY-mediated transcriptional control in DRG neurons; DS-lncRNA downregulation allows RALY to bind RNA Pol II and the Ehmt2 gene promoter more, enhancing Ehmt2 transcription and causing G9a-controlled downregulation of opioid receptors and Kcna2, contributing to neuropathic pain. RALY ChIP at Ehmt2 promoter, RNA Pol II interaction assay, DS-lncRNA overexpression/knockdown, DRG neuron behavioral pain model Advanced science Medium 34383386
2023 G9a binds the Fbxw7 promoter and represses Fbxw7 transcription via H3K9me2, inactivating the Notch suppressor pathway; this sustains glioma stem cell stemness and promotes an immunosuppressive tumor microenvironment. Dual-luciferase reporter assay, ChIP at Fbxw7 promoter, G9a inhibition, flow cytometry of immune cells in orthotopic glioma model CNS neuroscience & therapeutics Medium 36971192
2022 EHMT2 inhibition and NFYA overexpression cooperatively regulate ALDH2 expression; EHMT2 represses ALDH2 by H3K9 methylation, and ALDH2 overexpression activates the RAS/RAF pathway to confer paclitaxel resistance in NSCLC. ChIP at ALDH2 promoter, EHMT2 inhibitor, NFYA overexpression, RAF pathway analysis, xenograft models Molecular cancer Medium 35477569
2019 EHMT2 inhibition reduces H3K9me2 at the Beclin-1 promoter, allowing RNA Pol II and NF-κB recruitment and Beclin-1 transcriptional activation in a ROS-dependent manner; EHMT2 and DNMT1 cooperatively suppress Beclin-1, and combined inhibition synergistically induces autophagy. ChIP at Beclin-1 promoter, EHMT2 inhibitor (BIX-01294), DNMT1 inhibitor, NF-κB inhibition, ROS scavenging Oncotarget Medium 27174920
2022 Propionate promotes proteasomal degradation of EHMT2 through HECTD2 E3 ubiquitin ligase upregulation; EHMT2 degradation reduces H3K9me2 at the TNFAIP1 promoter, upregulating TNFAIP1 and inducing colorectal cancer cell apoptosis. EHMT2 protein stability assay, HECTD2 overexpression, ChIP at TNFAIP1 promoter, Bacteroides thetaiotaomicron culture medium treatment, 3D spheroid culture The ISME journal Medium 34972816
2017 G9a represses Twist1 and Twist2 transcription in osteogenic mesenchyme via H3K9me2 at regulatory regions of the Twist genes, timing cranial neural crest differentiation; G9a conditional KO in neural crest delays ossification and maintains Twist expression in osteogenic domains. ChIP at Twist1/2 regulatory regions in calvaria mesenchyme, Wnt1-Cre conditional G9a KO, BIX-01294 micromass cultures, in situ hybridization Journal of dental research High 28644763

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science (New York, N.Y.) 755 18988810
2011 H3K9 methyltransferase G9a and the related molecule GLP. Genes & development 458 21498567
2008 G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. The EMBO journal 318 18818694
2015 Functional Role of G9a Histone Methyltransferase in Cancer. Frontiers in immunology 199 26441991
2012 Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. The EMBO journal 163 23178591
2019 Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nature medicine 154 31270502
2014 The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes & development 131 24532712
2019 Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma. Hepatology (Baltimore, Md.) 110 30014490
2019 FOXO1 degradation via G9a-mediated methylation promotes cell proliferation in colon cancer. Nucleic acids research 101 30535125
2011 Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia (New York, N.Y.) 101 21847359
2007 Automethylation of G9a and its implication in wider substrate specificity and HP1 binding. Nucleic acids research 101 17962312
2015 Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression. Cancer research 100 25840984
2010 LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome research 99 21149390
2022 Human gut-microbiome-derived propionate coordinates proteasomal degradation via HECTD2 upregulation to target EHMT2 in colorectal cancer. The ISME journal 93 34972816
2015 EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 90 26320100
2017 Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy. Circulation 88 28778944
2019 Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents. European journal of medicinal chemistry 85 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 80 31095524
2019 Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma. Clinical epigenetics 79 31775874
2014 Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. The Journal of clinical investigation 78 24667637
2019 CNTN5-or EHMT2-human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks. eLife 72 30747104
2016 Alternative Splicing of G9a Regulates Neuronal Differentiation. Cell reports 69 26997278
2015 Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells. Clinical epigenetics 68 26300989
2018 Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway. Cell death & disease 66 29374157
2017 The Lysine Methyltransferase G9a in Immune Cell Differentiation and Function. Frontiers in immunology 66 28443098
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) 65 34383386
2014 Inhibition of H3K9 methyltransferase G9a repressed cell proliferation and induced autophagy in neuroblastoma cells. PloS one 65 25198515
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 EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms. The FEBS journal 57 34954891
2015 Down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation. Oncotarget 56 25595900
2020 Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis. Cancer discovery 55 32269030
2022 An EHMT2/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer. Molecular cancer 54 35477569
2020 G9a Plays Distinct Roles in Maintaining DNA Methylation, Retrotransposon Silencing, and Chromatin Looping. Cell reports 51 33113380
2016 G9a/GLP Complex Maintains Imprinted DNA Methylation in Embryonic Stem Cells. Cell reports 51 27052169
2010 A case study in cross-talk: the histone lysine methyltransferases G9a and GLP. Nucleic acids research 51 20159995
2019 G9a and histone deacetylases are crucial for Snail2-mediated E-cadherin repression and metastasis in hepatocellular carcinoma. Cancer science 50 31432592
2018 Interplay between EZH2 and G9a Regulates CXCL10 Gene Repression in Idiopathic Pulmonary Fibrosis. American journal of respiratory cell and molecular biology 50 29053336
2016 G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury. Molecular pain 50 27927796
2016 Human EHMT2/G9a activates p53 through methylation-independent mechanism. Oncogene 48 27452519
2016 Inhibition of EHMT2/G9a epigenetically increases the transcription of Beclin-1 via an increase in ROS and activation of NF-κB. Oncotarget 46 27174920
2021 Dual Targeting of G9a and DNA Methyltransferase-1 for the Treatment of Experimental Cholangiocarcinoma. Hepatology (Baltimore, Md.) 43 33222246
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
2020 G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer. Oncogene 42 33323965
2021 SPOP mutation induces DNA methylation via stabilizing GLP/G9a. Nature communications 40 34588438
2021 Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a. Life (Basel, Switzerland) 40 34685453
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 38 32174799
2016 G9a promotes proliferation and inhibits cell cycle exit during myogenic differentiation. Nucleic acids research 38 27229136
2017 Histone methyltransferase G9a modulates hepatic insulin signaling via regulating HMGA1. Biochimica et biophysica acta. Molecular basis of disease 36 29101051
2022 Discovery of the First-in-Class G9a/GLP Covalent Inhibitors. Journal of medicinal chemistry 35 35763668
2021 Lysine methyltransferase G9a is an important modulator of trained immunity. Clinical & translational immunology 35 33708384
2020 Targeting EHMT2/ G9a for cancer therapy: Progress and perspective. European journal of pharmacology 35 33347828
2021 Emerging role of G9a in cancer stemness and promises as a therapeutic target. Oncogenesis 33 34775469
2020 Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer. Journal of biochemical and molecular toxicology 33 33283949
2015 H3K9 methyltransferase G9a negatively regulates UHRF1 transcription during leukemia cell differentiation. Nucleic acids research 33 25765655
2012 Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a. Cell stem cell 33 22704517
2023 Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer. Gastroenterology 32 38065340
2022 PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing. Molecular cell 32 36476474
2018 G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst. eLife 32 29745895
2017 Methyltransferase G9a promotes cervical cancer angiogenesis and decreases patient survival. Oncotarget 31 28977928
2023 Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1. EMBO reports 30 37042626
2021 G9a/GLP targeting in MM promotes autophagy-associated apoptosis and boosts proteasome inhibitor-mediated cell death. Blood advances 30 33938943
2016 Mechanism of G9a inhibitor BIX‑01294 acting on U251 glioma cells. Molecular medicine reports 29 27748874
2023 G9a promotes immune suppression by targeting the Fbxw7/Notch pathway in glioma stem cells. CNS neuroscience & therapeutics 28 36971192
2019 Insights for the design of protein lysine methyltransferase G9a inhibitors. Future medicinal chemistry 27 31141392
2017 Structure-activity relationship studies of G9a-like protein (GLP) inhibitors. Bioorganic & medicinal chemistry 27 28662962
2016 The lysine methyltransferase Ehmt2/G9a is dispensable for skeletal muscle development and regeneration. Skeletal muscle 27 27239264
2014 Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2. Antioxidants & redox signaling 27 25365549
2019 Cyclin D1 integrates G9a-mediated histone methylation. Oncogene 26 30718920
2017 SATB2 suppresses non-small cell lung cancer invasiveness by G9a. Clinical and experimental medicine 26 28667416
2022 G9a Modulates Lipid Metabolism in CD4 T Cells to Regulate Intestinal Inflammation. Gastroenterology 25 36272457
2017 KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels. Scientific reports 25 28327608
2017 G9a controls placental vascular maturation by activating the Notch Pathway. Development (Cambridge, England) 25 28455378
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
2023 Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents. Journal of medicinal chemistry 21 36882960
2016 Depletion of G9a gene induces cell apoptosis in human gastric carcinoma. Oncology reports 21 27081761
2012 Abnormal histone H3K9 dimethylation but normal dimethyltransferase EHMT2 expression in cloned sheep embryos. Theriogenology 21 23058792
2023 ZFP462 safeguards neural lineage specification by targeting G9A/GLP-mediated heterochromatin to silence enhancers. Nature cell biology 20 36604593
2020 EHMT2 epigenetically suppresses Wnt signaling and is a potential target in embryonal rhabdomyosarcoma. eLife 20 33252038
2020 Increased Efficacy of Histone Methyltransferase G9a Inhibitors Against MYCN-Amplified Neuroblastoma. Frontiers in oncology 19 32537432
2020 Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines. Bioorganic & medicinal chemistry letters 19 32781218
2015 Inhibition of EHMT2 Induces a Robust Antiviral Response Against Foot-and-Mouth Disease and Vesicular Stomatitis Virus Infections in Bovine Cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 19 26418342
2020 Hypoxia-Inducible Lysine Methyltransferases: G9a and GLP Hypoxic Regulation, Non-histone Substrate Modification, and Pathological Relevance. Frontiers in genetics 18 33088284
2020 The Histone Methyltransferase Gene G9A Is Regulated by Nuclear Receptor 4A1 in Alveolar Rhabdomyosarcoma Cells. Molecular cancer therapeutics 18 33277444
2017 Methyltransferase G9A Regulates Osteogenesis via Twist Gene Repression. Journal of dental research 18 28644763
2015 Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a. PloS one 18 26192994
2022 Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis. Cancer research 17 35149587
2022 Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice. Cells 17 36010679
2017 Essential roles of G9a in cell proliferation and differentiation during tooth development. Experimental cell research 17 28527696
2017 The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer. Human pathology 17 29133140
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
2021 EHMT2 promotes the pathogenesis of hepatocellular carcinoma by epigenetically silencing APC expression. Cell & bioscience 16 34344448
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
2018 MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites. Scientific reports 16 30022091
2023 Histone-lysine N-methyltransferase EHMT2 (G9a) inhibition mitigates tumorigenicity in Myc-driven liver cancer. Molecular oncology 15 36896891
2023 HMGB1 neuroimmune signaling and REST-G9a gene repression contribute to ethanol-induced reversible suppression of the cholinergic neuron phenotype. Molecular psychiatry 15 37402853
2021 EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors. International journal of molecular sciences 15 34681949