Affinage

EHMT1

Histone-lysine N-methyltransferase EHMT1 · UniProt Q9H9B1

Length
1298 aa
Mass
141.5 kDa
Annotated
2026-06-09
62 papers in source corpus 30 papers cited in narrative 30 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

EHMT1 (GLP/KMT1D) is a SET-domain histone H3 lysine 9 methyltransferase that functions as the enzymatic core of repressive chromatin programs, depositing H3K9me1/me2 at target promoters to silence transcription across diverse developmental and disease contexts (PMID:24196706, PMID:26320100). Its in vivo activity depends on obligatory heterocomplex formation with EHMT2/G9a: Kleefstra syndrome patient missense mutations that impair catalysis also disrupt this heterocomplex, and catalytically dead EHMT2 variants act dominant-negatively to genocopy EHMT1 haploinsufficiency, defining the EHMT1–EHMT2 heterodimer as the critical functional unit [PMID:29459631, PMID:bio_10.1101_2025.09.25.678439]. Beyond nucleosomal H3, EHMT1 methylates linker histone H1 variants in a site- and variant-specific manner, generating H1.4K26me that recruits HP1 (PMID:20334638), and contributes to the DNA damage response by promoting MDC1-K45 methylation to expand activated ATM on damaged chromatin (PMID:30022091). EHMT1 is targeted to specific loci by partner transcription factors including PRDM16, Zfp281, and Wiz, through which it governs brown adipocyte versus muscle fate, exit from the naïve pluripotent state, and Foxp3 repression in T cells respectively (PMID:24196706, PMID:31782544, PMID:31362003). Its H3K9me2 activity maintains fetal-gene silencing in adult erythroid cells (γ-globin/HbF) and cardiomyocytes, and mediates activity-dependent transcriptional repression in neurons, where elevated EHMT1/2 represses BDNF, glutamate-receptor, and synaptic genes during homeostatic scaling and in models of Alzheimer's, autism, and Parkinson's disease (PMID:26320100, PMID:27893464, PMID:27373831, PMID:30668640, PMID:30659288, PMID:38472451). EHMT1 activity is itself regulated by LSD1-mediated demethylation of EHMT1-K450/K451, which reprograms its chromatin binding toward gene activation in cancer (PMID:37663929). Haploinsufficiency of EHMT1 causes Kleefstra syndrome, and domain-resolved patient studies establish that the ankyrin-repeat 'reader' function, rather than SET-domain catalysis alone, underlies the disorder's DNA-methylation episignature and core phenotype (PMID:15805155, PMID:39013458).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2005 Medium

    Established EHMT1 as a histone H3K9 methyltransferase and the causal gene for the 9q subtelomeric deletion (Kleefstra) neurodevelopmental syndrome, linking an epigenetic enzyme to human disease.

    Evidence Translocation breakpoint sequencing and embryonic/adult brain ISH in mouse

    PMID:15805155

    Open questions at the time
    • Did not resolve which catalytic or non-catalytic activity drives the phenotype
    • No molecular mechanism of target silencing defined
  2. 2010 High

    Extended EHMT1 substrate specificity beyond nucleosomal H3 to linker histone H1 variants, showing variant-specific marks with distinct reader/eraser consequences.

    Evidence In vitro HMT assays, MS site mapping, HP1 recruitment and JMJD2D demethylase assays

    PMID:20334638

    Open questions at the time
    • In vivo functional consequence of H1 methylation not established
    • Genomic loci of H1 methylation unmapped
  3. 2013 High

    Defined EHMT1 as an essential enzymatic and stabilizing subunit of the PRDM16 complex governing brown adipocyte identity, demonstrating partner-directed locus targeting.

    Evidence Adipose-specific conditional KO, PRDM16 Co-IP, H3K9me2/3 ChIP, in vivo thermogenesis

    PMID:24196706

    Open questions at the time
    • Structural basis of PRDM16–EHMT1 interaction unknown
    • Whether stabilization is catalysis-dependent unclear
  4. 2015 High

    Showed EHMT1/2-deposited H3K9me2 maintains developmental fetal-gene silencing, here γ-globin, identifying it as a therapeutic target for HbF induction.

    Evidence ChIP-seq, shRNA/CRISPR, UNC0638 inhibitor, RNA-seq, HbF flow cytometry in human CD34+ cells

    PMID:26320100

    Open questions at the time
    • Recruitment mechanism to globin locus not defined
    • Relative EHMT1 vs EHMT2 contribution not separated
  5. 2016 High

    Established EHMT1/2 as activity-dependent transcriptional repressors in neurons (synaptic scaling via BDNF) and in cardiomyocytes (fetal-gene suppression), generalizing the fetal-gene silencing role to post-mitotic tissues.

    Evidence shRNA/UNC0638, mEPSC electrophysiology, Bdnf-promoter ChIP; cardiac H3K9me2 ChIP-seq with miR-217 manipulation in vivo

    PMID:27373831 PMID:27893464

    Open questions at the time
    • Upstream signal coupling chromatin to activity not fully resolved
    • EHMT1-specific vs EHMT2-specific roles not dissected
  6. 2018 Medium

    Connected EHMT1/2 to the DNA damage response by methylating the adaptor MDC1 at K45, revealing a non-histone substrate that amplifies ATM signaling at break sites.

    Evidence Co-IP, in vitro methyltransferase mapping, immunofluorescence at DSBs and telomeres

    PMID:30022091

    Open questions at the time
    • EHMT1 vs EHMT2 dominance at MDC1-K45 unclear (EHMT2 dominant)
    • Single-lab; reciprocal validation limited
  7. 2018 High

    Resolved the molecular basis of Kleefstra syndrome mutations, showing patient SET-domain variants impair both catalysis and EHMT1–EHMT2 heterocomplex formation.

    Evidence In vitro HMT assays with mutagenesis, heterocomplex Co-IP, mouse GLP in vivo validation

    PMID:29459631

    Open questions at the time
    • Did not separate the reader-domain contribution from catalysis
    • Allele-specific phenotype severity not addressed
  8. 2019 Medium

    Identified sequence-specific transcription factors (Zfp281, Wiz) that recruit EHMT1 to defined enhancers/promoters, establishing how genomic targeting is achieved in pluripotency exit and Treg restriction.

    Evidence CRISPR screen and ChIP-seq (Zfp281); DNA pull-down MS, CRISPR KO and Foxp3-TSDR ChIP (Wiz)

    PMID:31362003 PMID:31782544

    Open questions at the time
    • Whether recruitment is universal or context-restricted unknown
    • Structural interface of TF–EHMT1 contacts undefined
  9. 2019 High

    Implicated elevated EHMT1/2 in neuropsychiatric disease by repressing synaptic and glutamate-receptor genes, with inhibition rescuing synaptic and behavioral deficits, identifying druggable disease axes.

    Evidence H3K9me2 ChIP-seq, electrophysiology, behavior, UNC0638/UNC0642, human postmortem tissue (Alzheimer's and Shank3/autism models)

    PMID:30659288 PMID:30668640

    Open questions at the time
    • Cause of EHMT1/2 elevation not established
    • Direct vs indirect target gene effects partially resolved
  10. 2019 Medium

    Placed Ehmt1 transcription under upstream control, showing a CDK2–NRF1 axis regulates Ehmt1 expression during meiotic prophase.

    Evidence CDK2 ChIP at Ehmt1 promoter, in vitro NRF1 kinase assay, conditional Cdk2 deletion in spermatocytes

    PMID:31350280

    Open questions at the time
    • Functional consequence of altered Ehmt1 levels in meiosis not assayed
    • Single-lab regulatory model
  11. 2019 Medium

    Linked EHMT1/2 H3K9me2 activity to cancer DNA-repair competence and therapy resistance, broadening its role into genome maintenance in tumors.

    Evidence RNA-seq, histone MS, HR/NHEJ functional assays, γH2AX IF, PDX model, shRNA and inhibitor in HGSOC

    PMID:31775874

    Open questions at the time
    • Mechanistic link between H3K9me2 and repair-gene silencing incomplete
    • EHMT1-specific contribution not isolated
  12. 2021 Medium

    Demonstrated EHMT1 supports tumor cell survival by repressing CDKN1A/p21 and pro-apoptotic CHOP, with depletion inducing arrest and apoptosis.

    Evidence siRNA, RNA-seq, FACS, spheroid assays (lung); H3K9me2 ChIP at CHOP promoter with double-knockdown epistasis (colorectal)

    PMID:34214254 PMID:35748228

    Open questions at the time
    • Whether p21 regulation is direct H3K9me2-mediated not shown
    • Single-lab tumor-context findings
  13. 2022 Medium

    Revealed catalysis-independent and indirect modes of EHMT1 action in cancer, including transcription-factor stabilization (C/EBPβ) rather than direct promoter binding.

    Evidence RNA-seq, ChIP showing no ALDH1A1 promoter binding, C/EBPβ stabilization assay, xenografts (ARMS)

    PMID:34897678

    Open questions at the time
    • Mechanism of C/EBPβ stabilization undefined
    • Generalizability beyond ARMS unknown
  14. 2023 High

    Separated EHMT1-specific from EHMT2-specific functions in vivo, showing EHMT1 is uniquely required for oocyte H3K9me1 and contributes to repression partly independently of EHMT2.

    Evidence Oocyte-specific Ehmt1, Ehmt2, and double cKO with multi-omics, IF, and proteomics

    PMID:36690445

    Open questions at the time
    • Molecular basis of EHMT1-exclusive H3K9me1 activity unclear
    • Whether monomethyl-specificity generalizes to other tissues unknown
  15. 2023 Medium

    Identified post-translational control of EHMT1 itself, where LSD1 demethylation of EHMT1-K450/K451 acts as a switch redirecting EHMT1 from repression toward oncogenic gene activation.

    Evidence PTM MS, before/after ChIP-seq, LSD1 demethylase assay, EHMT1/2 silencing/inhibition, in vivo proliferation/metastasis (prostate cancer)

    PMID:37663929

    Open questions at the time
    • Reader of the demethylated state not identified
    • Generality of the activation switch beyond prostate cancer untested
  16. 2024 Medium

    Reframed Kleefstra syndrome mechanism by showing the ankyrin-repeat reader domain, not SET-domain catalysis alone, drives the disease DNA-methylation episignature and core phenotype.

    Evidence In vitro variant testing and DNAm episignature analysis across a 209-individual cohort

    PMID:39013458

    Open questions at the time
    • How reader dysfunction propagates to genome-wide DNAm changes unknown
    • Relationship between episignature and clinical severity incomplete
  17. 2024 Medium

    Extended EHMT1/2-mediated synaptic-gene repression to Parkinson's disease, with inhibition rescuing synaptic and motor phenotypes.

    Evidence H3K9me2 ChIP at synaptic gene promoters, electrophysiology, shRNA, A-366 inhibitor, in vivo α-synuclein PFF mouse model

    PMID:38472451

    Open questions at the time
    • Trigger for EHMT1/2 elevation by α-synuclein not defined
    • Single-lab disease model
  18. 2025 Medium

    Bifurcated EHMT1 and EHMT2 genome-protection roles, identifying EHMT1-mediated LIG1 methylation as a driver of replication fork progression and alkylator resistance distinct from EHMT2's STING regulation.

    Evidence DNA fiber assays, LIG1 methylation assay, inhibitors/depletion, TNBC mouse models (preprint)

    PMID:37873068

    Open questions at the time
    • Preprint, not peer-reviewed
    • LIG1 methylation site and reader machinery not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How EHMT1's catalytic (writer) versus ankyrin-repeat (reader) activities, its non-histone substrate repertoire, and partner-directed recruitment are integrated into a single mechanistic model of locus selection across tissues remains unresolved.
  • No unified structural model of how reader and writer functions cooperate at target loci
  • Comprehensive non-histone substrate map lacking
  • Rules determining EHMT1-specific vs EHMT2-specific or heterocomplex-dependent activities incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7 GO:0140110 transcription regulator activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-73894 DNA Repair 3
Partners
EHMT2LSD1MDC1NF-KBNRF1PRDM16WIZZFP281
Complex memberships
EHMT1–EHMT2/G9a heteromeric methyltransferase complexPRDM16 transcriptional complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 EHMT1 (Eu-HMTase1) encodes a histone H3 lysine 9 methyltransferase (H3-K9 HMTase); disruption of the gene by a balanced translocation established that haploinsufficiency of EHMT1 causes 9q subtelomeric deletion syndrome, placing EHMT1 as the causal gene for this neurodevelopmental disorder. Translocation breakpoint sequencing; tissue in situ hybridization in mouse embryos and adult brain for spatio-temporal expression Journal of medical genetics Medium 15805155
2010 EHMT1 (Glp1/KMT1D) methylates linker histone H1 variants in vitro and in vivo; it methylates H1.2 at lysine 187 (C-terminal) and H1.4 at K26 (N-terminal) in a variant-specific manner. H1.4K26me can recruit HP1, whereas H1.2K187me cannot, and JMJD2D/KDM4 reverses only H1.4K26 methylation. In vitro histone methyltransferase assay; mass spectrometry mapping of methylation sites; in vivo validation; HP1 recruitment assay; JMJD2D demethylase assay Epigenetics & chromatin High 20334638
2013 EHMT1 is an essential lysine methyltransferase component of the PRDM16 transcriptional complex in brown adipocytes. Loss of EHMT1 in brown adipocytes causes demethylation of H3K9me2/3 at muscle-selective gene promoters, leading to loss of brown fat identity and induction of muscle differentiation in vivo. EHMT1 also stabilizes the PRDM16 protein and positively regulates the BAT thermogenic program. Adipose-specific deletion leads to reduced adaptive thermogenesis, obesity, and systemic insulin resistance. Adipose-specific conditional knockout mouse; co-immunoprecipitation (PRDM16 complex); ChIP for H3K9me2/3; in vivo thermogenesis assays; gene expression profiling Nature High 24196706
2015 EHMT1 and EHMT2 catalyze H3K9me2 at the γ-globin gene locus, contributing to fetal hemoglobin repression in adult erythroid cells. Pharmacological inhibition or shRNA-mediated knockdown of EHMT1/EHMT2 depletes H3K9me2 genome-wide with concomitant increase in H3K9Ac, and significantly induces γ-globin expression and HbF synthesis in primary human adult erythroid cells. ChIP-seq; shRNA knockdown; CRISPR/Cas9 knockout (Ehmt2 in MEL cells); small-molecule inhibitor (UNC0638); RNA-seq; HbF flow cytometry in primary human CD34+ cells Blood High 26320100
2016 EHMT1 plays a cell-autonomous role in homeostatic synaptic scaling (scaling up) in neurons. Chronic activity deprivation increases neuronal H3K9me2 (catalytic product of EHMT1/2). Genetic knockdown or pharmacological blockade of EHMT1/2 prevents H3K9me2 increase and blocks synaptic scaling up. EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter precedes BDNF repression during synaptic scaling up both in vitro and in vivo. Genetic knockdown (shRNA); pharmacological inhibition (UNC0638); electrophysiology (mEPSC recording); ChIP for H3K9me2 at Bdnf promoter; in vivo sensory deprivation Neuron High 27373831
2016 EHMT1 and EHMT2 (EHMT1/2) maintain H3K9me2 in adult cardiomyocytes to suppress fetal gene reexpression. In pathological cardiac hypertrophy, miR-217 reduces EHMT1/2 expression, causing pervasive loss of H3K9me2 and reexpression of fetal genes. miR-217-mediated, genetic, or pharmacological inactivation of EHMT1/2 is sufficient to promote pathological hypertrophy, whereas suppression of this pathway protects against pathological hypertrophy. H3K9me2 and H3K27me3 ChIP-seq in physiological vs. pathological rat hypertrophy; miR-217 overexpression/inhibition; genetic and pharmacological EHMT1/2 inactivation in vitro and in vivo mouse models The Journal of clinical investigation High 27893464
2018 EHMT1 interacts with MDC1 (the DNA damage response adaptor) in a manner facilitated by DNA damage-initiated ATM signaling. EHMT2 dominantly methylates MDC1 at lysine 45. This methylation promotes MDC1–ATM interaction to expand activated ATM on damaged chromatin and at dysfunctional telomeres, enabling accumulation of DDR factors 53BP1 and RAP80 at DSB sites. Co-immunoprecipitation; in vitro methyltransferase assay mapping MDC1-K45 methylation; immunofluorescence at DSB sites; laser-induced DNA damage; EHMT1/2 inhibitor treatment Scientific reports Medium 30022091
2018 EHMT1 missense mutations C1073Y and R1197W (identified in Kleefstra syndrome patients) severely impair in vitro histone methyltransferase (HMT) activity. These mutants also show defective heterocomplex formation with EHMT2/G9a, which is essential for in vivo HMT function. Corresponding substitutions in mouse GLP confirm impaired in vivo function. In vitro HMT activity assay; heterocomplex co-immunoprecipitation; in vivo GLP functional assay in mouse cells Journal of human genetics High 29459631
2019 EHMT1 and EHMT2 are elevated in Alzheimer's disease (FAD mouse model and human postmortem PFC), leading to increased H3K9me2 at glutamate receptor gene promoters (ChIP-seq), reduced AMPA and NMDA receptor transcription/expression, and impaired excitatory synaptic function. EHMT1/2 inhibition reverses histone hypermethylation, restores glutamate receptor expression and synaptic function, and rescues recognition, working, and spatial memory deficits. ChIP-seq (H3K9me2); immunoblot; electrophysiology; behavioral testing; EHMT1/2 inhibitor treatment; human postmortem tissue analysis Brain : a journal of neurology High 30668640
2019 EHMT1 and EHMT2 are selectively elevated in the PFC of Shank3-deficient (autism model) mice and autistic human postmortem brains, leading to increased H3K9me2. EHMT1/2 inhibition or knockdown in PFC rescues autism-like social deficits and restores NMDAR-mediated synaptic function. Arc (activity-regulated cytoskeleton-associated protein) was identified as a causal downstream target mediating the rescue of NMDAR function and social behavior. Immunoblot; ChIP; electrophysiology (NMDAR-EPSCs); behavioral assays (social interaction); EHMT1/2 inhibitor (UNC0642); shRNA knockdown; RNA-seq in PFC Molecular psychiatry High 30659288
2019 The zinc finger transcription factor Zfp281 recruits EHMT1 to enhancers and promoters in mouse ESCs/EpiSCs, activating H3K9 methylation. Genetic gain- and loss-of-function experiments showed EHMT1 acts downstream of Zfp281 to drive exit from the naïve ESC state and restrict reprogramming of EpiSCs. Comparative CRISPR screen; ChIP-seq (Zfp281 binding); genetic gain-of-function and loss-of-function (ESC/EpiSC interconversion assays) The EMBO journal Medium 31782544
2019 CDK2 binds to the Ehmt1 promoter through interaction with the NRF1 transcription factor. CDK2-mediated phosphorylation of NRF1 at two distinct serine residues negatively regulates NRF1 DNA binding activity in vitro. Induced deletion of Cdk2 in spermatocytes increases Ehmt1 expression, establishing an NRF1/Ehmt1 regulatory axis controlling H3K9 methylation during meiotic prophase I. ChIP (CDK2 at Ehmt1 promoter); in vitro kinase assay (NRF1 phosphorylation); conditional Cdk2 deletion in spermatocytes; gene expression analysis The Journal of cell biology Medium 31350280
2019 Wiz transcription factor recruits EHMT1 to the Foxp3 TSDR (Treg-specific demethylated region) in conventional T cells, depositing H3K9me2 to repress Foxp3 expression and counteract iTreg differentiation. CRISPR/Cas9 knockout of either Ehmt1 or Wiz leads to loss of H3K9me2 at the Foxp3 TSDR and enhanced Foxp3 expression during iTreg differentiation. DNA pull-down with mass spectrometry (Wiz-EHMT1 interaction); CRISPR/Cas9 knockout; ChIP (H3K9me2 at Foxp3 TSDR); flow cytometry (Foxp3 expression) Journal of molecular biology Medium 31362003
2019 EHMT1/2 maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma (HGSOC) through H3K9me2-mediated epigenetic silencing. Disruption of EHMT1/2 ablates both homologous recombination (HR) and non-homologous end joining (NHEJ), increases DNA damage (γH2AX), and alters cell cycle distribution. EHMT1/2 inhibition sensitizes HGSOC cells to PARPi. RNA-seq; mass spectrometry (histone modification profiling); functional DNA repair assays (HR/NHEJ); immunofluorescence (γH2AX); flow cytometry (cell cycle/apoptosis); in vivo PDX model; genetic (shRNA) and pharmacological EHMT1/2 inhibition Clinical epigenetics Medium 31775874
2017 The Kleefstra syndrome protein EHMT1 (via its Drosophila ortholog G9a) is required in the mushroom body for short-term memory. G9a and the KMT2C ortholog trr share common direct targets including Arc1 (key synaptic plasticity regulator), and their transcriptional programs show significant overlap in neurons, indicating functional convergence in an ID/ASD-related network. Drosophila genetic analysis (mushroom body-specific knockdown, G9a null); ChIP-seq (trr); transcriptional profiling (RNA-seq of pan-neuronal knockdowns); behavioral memory assay PLoS genetics Medium 29069077
2021 EHMT1 knockdown in lung cancer cells (A549, H1299) induces G1 cell cycle arrest and apoptosis through upregulation of CDKN1A (p21). In 3D spheroid culture, EHMT1 knockdown reduces spheroid aggregation and upregulates CDKN1A while downregulating E-cadherin. siRNA knockdown; RNA-seq; FACS (cell cycle, apoptosis); 3D spheroid culture; immunoblot Molecular oncology Medium 34214254
2022 EHMT1 activates ALDH1A1 expression in alveolar rhabdomyosarcoma (ARMS) by stabilizing the transcription factor C/EBPβ (rather than by direct promoter binding). EHMT1 suppression impairs motility, induces differentiation, and reduces tumor progression in vivo. ALDH1A1 inhibition mimics EHMT1 depletion, linking EHMT1 to cancer stem cell maintenance. RNA-seq (EHMT1-depleted ARMS cells); ChIP (showing EHMT1 does not bind ALDH1A1 promoter); C/EBPβ stabilization assay; xenograft mouse model; ALDH activity inhibition The Journal of pathology Medium 34897678
2022 EHMT1 epigenetically silences CHOP expression via H3K9me2 deposition at the CHOP gene promoter in colorectal cancer cells. EHMT1 knockdown induces CHOP-mediated apoptosis, confirmed by co-knockdown of EHMT1 and CHOP reversing the apoptosis phenotype. ChIP (anti-H3K9me2 at CHOP promoter); siRNA knockdown (EHMT1 alone and EHMT1+CHOP double KD); RNA-seq; apoptosis assays Molecules and cells Medium 35748228
2023 In mouse oocytes, EHMT1 is uniquely required for H3K9me1 deposition (H3K9me1 is depleted only upon EHMT1 loss, not EHMT2 loss), while H3K9me2 and H3K9me2-enriched domains are equally reduced by loss of either EHMT1 or EHMT2. EHMT1 contributes to transcriptional repression in the oocyte partially independently of EHMT2, and is essential for oocyte maturation, developmental competence, and avoidance of mid-gestation embryonic lethality after fertilization. Oocyte-specific conditional knockout (Ehmt1 cKO, Ehmt2 cKO, Ehmt1/2 cDKO); immunofluorescence; multi-omics (transcriptome, DNA methylome); mass spectrometry proteomics Genome research High 36690445
2023 EHMT1 protein is methylated at lysine 450 and 451 residues in prostate cancer cells; LSD1 demethylates lysine 450. Concurrent demethylation of both lysine residues greatly expands EHMT1 chromatin binding capacity, reprogramming EHMT1's transcriptional activity toward activation of oncogenic signaling pathways. This dual-lysine demethylation acts as a molecular switch for oncogenic transcriptional reprogramming. Mass spectrometry (PTM identification at K450/K451); ChIP-seq (before/after demethylation); LSD1 demethylase assay; EHMT1/2 silencing and small-molecule inhibition; in vitro and in vivo proliferation/metastasis assays Cancer research communications Medium 37663929
2024 Disruption of the EHMT1 ankyrin repeat domain 'reader' function (by protein-altering variant) produces the Kleefstra syndrome-specific DNA methylation (DNAm) signature and milder phenotype, while disruption of only the SET domain 'writer' methyltransferase activity does not produce the KS1 DNAm signature or typical KS1 phenotype. N-terminal truncating variants also result in mild phenotype without the DNAm signature. In vitro variant functional testing; DNAm signature analysis (episignature); comprehensive in silico analysis; cohort of 209 individuals with EHMT1 variants American journal of human genetics Medium 39013458
2024 In a Parkinson's disease α-synuclein PFF model, EHMT1 and EHMT2 are increased and mediate elevated H3K9me2 at promoters of synaptic genes (SNAP25, PSD95, Synapsin 1, vGLUT1), causing their transcriptional repression and synaptic damage. EHMT1/2 inhibition (A-366) or shRNA suppresses histone methylation, alleviates synaptic damage in primary neurons, and rescues synaptic damage and motor impairment in PFF-injected mice. ChIP (H3K9me2 at synaptic gene promoters); immunoblot; electrophysiology (synapse number); shRNA knockdown; pharmacological inhibition (A-366); in vivo PFF mouse model; behavioral motor assays Cellular and molecular life sciences Medium 38472451
2017 The EHMT1 p.P809L missense variant (within the ankyrin repeat domain conserved TPLX motif) leads to protein misfolding and aberrant target (histone mark) recognition, confirmed by molecular dynamics simulation and experimental far UV circular dichroism spectroscopy and intrinsic protein fluorescence studies. Molecular dynamics simulation; far UV circular dichroism spectroscopy; intrinsic protein fluorescence of recombinant EHMT1 P809L The Journal of biological chemistry Medium 28057753
2019 Co-crystal structure of the EHMT1/GLP SET domain in complex with a novel benzodiazepine-scaffold inhibitor (EML741/12a) was determined, providing the structural basis for GLP active-site inhibitor interactions and informing further inhibitor development. Co-crystal structure determination (X-ray crystallography); in vitro methyltransferase inhibition assay; PAMPA permeability assay Journal of medicinal chemistry High 30753076
2023 EHMT1 and EHMT2 repress genes regulating cell death and electrical properties in oligodendrocyte progenitor cells (OPCs). Genetic deletion of Ehmt1/Ehmt2 in the oligodendrocyte lineage leads to higher levels of cholinergic muscarinic receptors, fewer oligodendrocyte lineage cells, and lower MBP levels. H3K9me2 levels increase in proliferating OPCs following optogenetic stimulation of neuronal activity. Lineage-specific conditional knockout (Ehmt1/Ehmt2 in OPCs); pharmacological EHMT inhibition; RNA-seq; immunofluorescence; optogenetic neuronal stimulation Glia Medium 40134232
2025 EHMT1-mediated methylation of LIG1 (DNA ligase 1) is the primary mechanism by which EHMT1 (distinct from EHMT2) promotes replication fork progression and alkylating agent resistance; loss of EHMT1-mediated LIG1 methylation causes ATM-mediated replication fork slowdown and accumulation of single-stranded replication gaps. EHMT2 (separately from EHMT1) regulates STING1 promoter CpG methylation via an EHMT2-UHRF1 axis, with EHMT2 loss elevating STING expression and promoting anti-tumor immune response. EHMT1/2 inhibitors and depletion; DNA fiber assay (replication fork); cytosolic DNA/STING assays; mouse models of TNBC; LIG1 methylation assay; UHRF1 depletion; bisulfite sequencing (STING1 promoter CpG) bioRxivpreprint Medium 37873068
2025 EHMT1 (as part of the GLP/G9a heteromeric complex) mediates H3K9 methylation essential for normal meiotic and developmental processes. Patient-derived EHMT2 variants that are catalytically incompetent (unable to bind histone H3 tail or SAM) exert dominant-negative effects on GLP/G9a complexes, genocopying EHMT1 haploinsufficiency, underscoring that the EHMT1–EHMT2 heterocomplex enzymatic activity is the critical functional unit. In vitro enzymatic assay (H3 tail and SAM binding); heterozygous knock-in mouse (patient-derived EHMT2 variant); episignature analysis; histone modification profiling; transcriptomics bioRxivpreprint Medium bio_10.1101_2025.09.25.678439
2023 EHMT1 depletion in RPE1 cells alters morphology and distribution of the Golgi apparatus, lysosomes, and cell adhesion components, increases centriolar satellite detection (suggesting a role in centrosome function), and reduces cell migration capacity. siRNA depletion; immunofluorescence (Golgi, lysosomes, centrosome markers); migration assay Cellular signalling Low 37257768
2020 EHMT1 regulates parvalbumin-positive (PV+) interneuron maturation in sensory cortical areas. Ehmt1+/- mice show a delay in PV+ neuron maturation early in sensory development, with region/layer-specific variability. A reduced GABA release probability at putative PV+ synapses was observed in auditory cortex, indicating that Ehmt1 haploinsufficiency impairs inhibitory circuit maturation. Immunofluorescence (PV+ cell counting across development); patch-clamp electrophysiology (GABAergic transmission in auditory cortex); Ehmt1+/- mouse model Brain structure & function Medium 32975655
2023 G9a (EHMT2) and GLP (EHMT1) are present in a protein complex with NF-κB in adipocytes treated with TNFα. Loss of G9a/GLP via siRNA enhances TNFα-induced lipolysis and inflammatory gene expression in adipocytes, placing EHMT1 in a TNFα/NF-κB signaling context in adipocytes. siRNA knockdown; co-immunoprecipitation (EHMT1/EHMT2 with NF-κB); lipolysis assay; inflammatory gene expression (qPCR) Biology Low 37237488

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. American journal of human genetics 293 16826528
2013 EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 279 24196706
2012 Disruption of an EHMT1-associated chromatin-modification module causes intellectual disability. American journal of human genetics 201 22726846
2009 Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. Journal of medical genetics 162 19264732
2005 Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. Journal of medical genetics 142 15805155
2019 Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease. Brain : a journal of neurology 132 30668640
2017 Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder. PLoS genetics 127 29069077
2016 The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. The Journal of clinical investigation 102 27893464
2015 EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 91 26320100
2010 Histone H1 variant-specific lysine methylation by G9a/KMT1C and Glp1/KMT1D. Epigenetics & chromatin 85 20334638
2019 Histone methyltransferases EHMT1 and EHMT2 (GLP/G9A) maintain PARP inhibitor resistance in high-grade serous ovarian carcinoma. Clinical epigenetics 82 31775874
2016 Histone Methylation by the Kleefstra Syndrome Protein EHMT1 Mediates Homeostatic Synaptic Scaling. Neuron 72 27373831
2019 Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice. Molecular psychiatry 68 30659288
2022 EHMT1/EHMT2 in EMT, cancer stemness and drug resistance: emerging evidence and mechanisms. The FEBS journal 60 34954891
2019 Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure. Journal of medicinal chemistry 54 30753076
2015 Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression. PloS one 44 25812118
2021 EHMT1 knockdown induces apoptosis and cell cycle arrest in lung cancer cells by increasing CDKN1A expression. Molecular oncology 32 34214254
2019 Zfp281 orchestrates interconversion of pluripotent states by engaging Ehmt1 and Zic2. The EMBO journal 27 31782544
2016 Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance. Gene 26 27651234
2014 Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects. Molecular autism 21 25400900
2024 Comprehensive EHMT1 variants analysis broadens genotype-phenotype associations and molecular mechanisms in Kleefstra syndrome. American journal of human genetics 19 39013458
2018 EHMT1 mosaicism in apparently unaffected parents is associated with autism spectrum disorder and neurocognitive dysfunction. Molecular autism 19 29416845
2017 A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. The Journal of biological chemistry 17 28057753
2017 Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation. Scientific reports 17 28071689
2013 Analysis of EHMT1 expression and its correlations with clinical significance in esophageal squamous cell cancer. Molecular and clinical oncology 17 24649311
2012 A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring. European journal of human genetics : EJHG 17 23232695
2023 Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptional repression during oogenesis. Genome research 16 36690445
2018 MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites. Scientific reports 16 30022091
2019 9q34.3 microduplications lead to neurodevelopmental disorders through EHMT1 overexpression. Neurogenetics 15 31209758
2019 Inhibition of Histone Methyltransferases EHMT1/2 Reverses Amyloid-β-Induced Loss of AMPAR Currents in Human Stem Cell-Derived Cortical Neurons. Journal of Alzheimer's disease : JAD 14 31322566
2019 CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I. The Journal of cell biology 14 31350280
2016 A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. Molecular genetics & genomic medicine 13 28361099
2011 Characterization of a novel transcript of the EHMT1 gene reveals important diagnostic implications for Kleefstra syndrome. Human mutation 13 21538692
2022 EHMT1 promotes tumor progression and maintains stemness by regulating ALDH1A1 expression in alveolar rhabdomyosarcoma. The Journal of pathology 12 34897678
2022 CRISPR single base editing, neuronal disease modelling and functional genomics for genetic variant analysis: pipeline validation using Kleefstra syndrome EHMT1 haploinsufficiency. Stem cell research & therapy 12 35139903
2020 EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas. Brain structure & function 12 32975655
2014 Intragenic duplication of EHMT1 gene results in Kleefstra syndrome. Molecular cytogenetics 12 25349628
2018 Biochemical validation of EHMT1 missense mutations in Kleefstra syndrome. Journal of human genetics 10 29459631
2024 Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model. Cellular and molecular life sciences : CMLS 9 38472451
2022 Epigenetic Silencing of CHOP Expression by the Histone Methyltransferase EHMT1 Regulates Apoptosis in Colorectal Cancer Cells. Molecules and cells 9 35748228
2019 Recruitment of Histone Methyltransferase Ehmt1 to Foxp3 TSDR Counteracts Differentiation of Induced Regulatory T Cells. Journal of molecular biology 9 31362003
2016 Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance. Stem cell research 9 27789404
2016 Enrichment of small pathogenic deletions at chromosome 9p24.3 and 9q34.3 involving DOCK8, KANK1, EHMT1 genes identified by using high-resolution oligonucleotide-single nucleotide polymorphism array analysis. Molecular cytogenetics 9 27891178
2024 EHMT1/2 Inhibition Promotes Regression of Therapy-Resistant Ovarian Cancer Tumors in a CD8 T-cell-Dependent Manner. Molecular cancer research : MCR 8 39136655
2018 Hypogonadotropic Hypogonadism and Kleefstra Syndrome due to a Pathogenic Variant in the EHMT1 Gene: An Underrecognized Association. Case reports in endocrinology 8 30370152
2011 Constitutional tandem duplication of 9q34 that truncates EHMT1 in a child with ganglioglioma. Pediatric blood & cancer 8 21681934
2021 Clinical phenotypes and molecular findings in ten Chinese patients with Kleefstra Syndrome Type 1 due to EHMT1 defects. European journal of medical genetics 7 34265435
2020 Epigenetic priming by EHMT1/EHMT2 in acute lymphoblastic leukemia induces TP53 and TP73 overexpression and promotes cell death. Toxicology in vitro : an international journal published in association with BIBRA 7 32889036
2016 Reversible white matter lesions associated with mutant EHMT1 and Kleefstra syndrome. Neurology. Genetics 7 27123477
2023 TNFα Effects on Adipocytes Are Influenced by the Presence of Lysine Methyltransferases, G9a (EHMT2) and GLP (EHMT1). Biology 6 37237488
2020 Impairments in sensory-motor gating and information processing in a mouse model of Ehmt1 haploinsufficiency. Brain and neuroscience advances 6 32954001
2023 Cell consequences of loss of function of the epigenetic factor EHMT1. Cellular signalling 4 37257768
2022 Potential Therapeutics Targeting Upstream Regulators and Interactors of EHMT1/2. Cancers 4 35740522
2023 Demethylation of EHMT1/GLP Protein Reprograms Its Transcriptional Activity and Promotes Prostate Cancer Progression. Cancer research communications 2 37663929
2023 Tourette-like syndrome secondary to Kleefstra syndrome 1 with a de novo microdeletion in the EHMT1 gene. BMC neurology 2 37817104
2023 Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy. bioRxiv : the preprint server for biology 2 37873068
2023 A multi-layered computational structural genomics approach enhances domain-specific interpretation of Kleefstra syndrome variants in EHMT1. Computational and structural biotechnology journal 2 37954151
2025 The Histone Methyltransferases EHMT1 and EHMT2 Repress the Expression of Genes Related to Excitability and Cell Death in Oligodendrocyte Progenitors. Glia 1 40134232
2025 A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review. Genes 1 40428343
2025 EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression. British journal of cancer 0 40467997
2023 A Multi-Layered Computational Structural Genomics Approach Enhances Domain-Specific Interpretation of Kleefstra Syndrome Variants in EHMT1. bioRxiv : the preprint server for biology 0 37786696
2023 Reanalysis of Chromosomal Microarray Data Using a Smaller Copy Number Variant Call Threshold Identifies Four Cases with Heterozygous Multiexon Deletions of ARID1B, EHMT1, and FOXP1 Genes. Molecular syndromology 0 37901861

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