Alternative titles; symbols
HGNC Approved Gene Symbol: EHMT1
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:137,619,005-137,836,127 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q34.3 | Kleefstra syndrome 1 | 610253 | Autosomal dominant | 3 |
G9A (EHMT2; 604599) and GLP (EHMT1) form a protein complex that is a key histone H3 (see 602810) lys9 (H3K9) methyltransferase (Ueda et al., 2006).
Ogawa et al. (2002) identified the components of the E2F6 (602944) complex, which represses transcription. Although histone acetylase and deacetylase activities were not detected in the E2F6 complex, methyltransferase activity was. Ogawa et al. (2002) identified euchromatic histone methyltransferase-1 as a component of the E2F6 complex. The 1,267-amino acid EU-HMTase-1 protein contains ankyrin repeats and a SET domain. EU-HMTase-1 shares 63% sequence similarity with NG36/G9A. EU-HMTase-1 exhibited histone methyltransferase activity with a specificity for histone H3 in core histones, whereas it hardly methylated nucleosomes, suggesting that other subunits in the E2F6 complex are required for modification of nucleosomal substrates. Ogawa et al. (2002) demonstrated that lysine-9 of histone H3 is the target of euchromatic histone methyltransferase-1.
Kleefstra et al. (2006) stated that the EHMT1 gene contains 28 exons. The initiation ATG occurs in exon 2.
Stumpf (2020) mapped the EHMT1 gene to chromosome 9q34.3 based on an alignment of the EHMT1 sequence (GenBank BC047504) with the genomic sequence (GRCh38).
Using mass spectrometry, Ueda et al. (2006) identified Wiz (619715) as a component of the G9a/Glp complex in mouse embryonic stem cells (ESCs). Wiz interacted with both G9a and Glp in the complex. The interactions were mediated by the SET domains of G9a and Glp and by zinc finger motif-6 of Wiz. Knockout analysis revealed that binding of Wiz to both G9a and Glp was more stable in the G9a/Glp heteromeric complex and that Wiz, in turn, contributed to the stability of G9a in the complex. The authors also identified 2 PxDLS-like putative CTBP (see 602618)-binding motifs in Wiz, which connected the G9a/Glp heteromeric complex with CTBP corepressors.
Ohno et al. (2013) demonstrated that EHMT1 is an essential brown adipose tissue (BAT)-enriched lysine methyltransferase in the PRDM16 (605557) transcriptional complex and controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes causes a severe loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 lysine 9 (H3K9me2 and 3) of the muscle-selective gene promoters. Conversely, EHMT1 expression positively regulates the BAT-selective thermogenic program by stabilizing the PRDM16 protein. Notably, adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity, and systemic insulin resistance. Ohno et al. (2013) concluded that EHMT1 is an essential enzymatic switch that controls brown adipose cell fate and energy homeostasis.
Using mouse ESCs, Maier et al. (2015) confirmed interaction between 2 major repressive histone methyltransferase complexes, PRC2 (see EZH1, 601674) and G9a-Glp. Moreover, the complexes shared several interaction partners, including Znf518a (617733) and Znf518b (617734). In vitro, Znf518b interacted directly with G9a and with the 2 alternative PRC2 methyltransferase subunits, Ezh1 and Ezh2 (601573). Knockdown of Znf518b in mouse ESCs reduced global H3K9 dimethylation. Maier et al. (2015) concluded that ZNF518B may mediate association between PRC2 and G9A-GLP and regulate G9A-GLP activity.
Using mass spectrometry, Bian et al. (2015) identified ZNF644 (614159) and WIZ as subunits of the G9A/GLP complex in 293T cells. The N terminus of ZNF644 and the C terminus of WIZ interacted with the complex through the transcription activation domains of G9A and GLP, respectively. ZNF644 and WIZ bound to chromatin and facilitated localization of the G9A/GLP complex to chromatin. Chromatin immunoprecipitation-sequencing analysis showed that WIZ and ZNF644 associated with G9A at the promoter regions of specific loci and targeted G9A and GLP to genomic loci for transcriptional repression.
Yuan et al. (2020) reported a conserved epigenetic mechanism underlying healthy aging. Through genomewide RNA interference-based screening of genes that regulate behavioral deterioration in aging C. elegans, they identified 59 genes as potential modulators of the rate of age-related behavioral deterioration. Among these modulators, they found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine-9 (H3K9) methyltransferase, SET6, accelerated behavioral deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism was conserved in cultured mouse neurons and human cells. Examination of human databases showed that expression of the human orthologs of these C. elegans regulators, BAZ2B (605683) and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer disease (104300). Furthermore, ablation of Baz2b, the mouse ortholog of BAZ2, attenuated age-dependent body weight gain and prevented cognitive decline in aging mice.
The chromosome 9q subtelomeric deletion syndrome, or Kleefstra syndrome-1 (KLEFS1; 610253), is a mental retardation syndrome that was thought to be caused by small interstitial deletions in the 9q subtelomeric region. Kleefstra et al. (2005) characterized the breakpoints in a female with a balanced translocation t(X;9)(p11.23;q34.3) and found that the chromosome breakpoint disrupted the EHMT1 gene in intron 9. The patient presented typical features of 9q subtelomeric deletion syndrome, which suggested that the core phenotype of this entity is due to haploinsufficiency of EHMT1. Kleefstra et al. (2006) performed a comprehensive mutation analysis of the EHMT1 gene in 23 patients with clinical presentations consistent with 9q subtelomeric deletion syndrome. Three patients had microdeletions that comprised the EHMT1 gene; 1 interstitial deletion reduced the critical region for this syndrome. Two patients had de novo mutations, a nonsense mutation and a frameshift mutation, in the EHMT1 gene (607001.0001-607001.0002). These results appeared to establish that haploinsufficiency of EHMT1 is causative for the 9q subtelomeric deletion syndrome.
In 6 of 24 patients with a clinical phenotype consistent with 9q deletion syndrome who had normal chromosome studies, Kleefstra et al. (2009) identified 6 different intragenic mutations in the EHMT1 gene (see, e.g., C1042Y, 607001.0003 and R260X, 607001.0004). There were 2 nonsense mutations, a deletion, 2 splice site mutations, and 1 missense mutation in a highly conserved residue. A comparison of the phenotype between these 6 patients and 16 additional patients with larger deletions of 9q showed no genotype/phenotype correlations. Kleefstra et al. (2009) concluded that haploinsufficiency for EHMT1 is the basis for the phenotypic features in this disorder.
Schaefer et al. (2009) found that conditional ablation of Ehmt2 (604599) or Ehmt1 in postnatal mouse forebrain neurons caused a reduction in euchromatic H3K9 methylation in the forebrain and upregulation/derepression of neuronal and nonneuronal genes (e.g., AFP; 104150), including those involved in developmental stage-dependent gene expression (e.g., Dach2; 300608). These changes were not associated with alterations in neuronal architecture or electrophysiologic features. Mice with postnatal knockout of Ehmt1 or Ehmt2 in the forebrain showed decreased exploratory behavior in a novel environment and had a decrease in the preference for sucrose solution compared to wildtype mice, the latter of which may indicate an underlying dysfunction in motivation/reward. Both Ehmt2-null and Ehmt1-null mice became obese. Ehmt1-null mice also showed defects in contextual and cued fear conditioning, indicating a problem with learning and memory. Mice lacking Ehmt2 specifically in Drd1 (126449)- or Drd2 (126450)-expressing neurons in the striatum showed altered locomotor and behavioral responses to Drd-specific receptor agonist or antagonists, reflecting reductions of cell type-specific activity. The changes in these mice resembled the features of the human chromosome 9q34.3 deletion syndrome. Schaefer et al. (2009) concluded that Ehmt1 and Ehmt2 are key regulators of cognition and adaptive behavior in adult mice through regulation of transcriptional homeostasis.
In a patient (P4) with clinical features of the 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2006) identified a heterozygous 3409C-T transition (c.3409C-T, NM_024757) in exon 24 of the EHMT1 gene that caused an arg1137-to-stop substitution (R1137X).
In a patient (P5) with clinical features of the 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2006) identified a heterozygous 13-bp deletion in exon 8 of the EHMT1 gene (c.1320_1332del13, NM_024757). The deletion resulted in a frameshift (P442fs) and a premature stop that predicted a mutant protein of 526 amino acids.
In a 20-year-old woman (patient 20) with a phenotype consistent with chromosome 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2009) identified a de novo heterozygous c.3125G-A transition (c.3125G-A, NM_024757.3) in the EHMT1 gene, resulting in a cys1042-to-tyr (C1042Y) substitution in a highly conserved residue in the pre-SET domain of the protein. Protein modeling predicted that the substitution would abolish a strong cysteine-zinc interaction and interfere with the local conformation of the pre-SET domain. The phenotype was fully compatible with the deletion syndrome, and included severe psychomotor retardation, hypotonia, and characteristic facial features of midface hypoplasia, synophrys, and eversion of the lower lip. She also had pulmonary stenosis. Kleefstra et al. (2009) postulated loss of protein function and haploinsufficiency rather than a dominant-negative effect.
In a 19-year-old man (patient 19) with a phenotype consistent with chromosome 9q subtelomeric deletion syndrome (KLEFS1; 610253), Kleefstra et al. (2009) identified a de novo heterozygous c.778C-T transition (c.778C-T, NM_024757.3) in the EHMT1 gene, resulting in an arg260-to-ter (R260X) substitution, predicted to result in nonsense-mediated mRNA decay. The man had mental retardation, seizures, and characteristic facial abnormalities.
Bian, C., Chen, Q., Yu, X. The zinc finger proteins ZNF644 and WIZ regulate the G9a/GLP complex for gene repression. eLife 4: e05606, 2015. Note: Erratum: eLife 4: e08168, 2015. [PubMed: 25789554] [Full Text: https://doi.org/10.7554/eLife.05606]
Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A., Genevieve, D., Cormier-Daire, V., van Esch, H., Fryns, J.-P., Hamel, B. C. J., Sistermans, E. A., de Vries, B. B. A., van Bokhoven, H. Loss-of-function mutations in Euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am. J. Hum. Genet. 79: 370-377, 2006. [PubMed: 16826528] [Full Text: https://doi.org/10.1086/505693]
Kleefstra, T., Smidt, M., Banning, M. J. G., Oudakker, A. R., Van Esch, H., de Brouwer, A. P., Nillesen, W., Sistermans, E. A., Hamel, B. C., de Bruijn, D., Fryns, J.-P., Yntema, H. G., Brunner, H. G., de Vries, B. B. A., van Bokhoven, H. Disruption of the gene euchromatin histone methyl transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome. J. Med. Genet. 42: 299-306, 2005. [PubMed: 15805155] [Full Text: https://doi.org/10.1136/jmg.2004.028464]
Kleefstra, T., van Zelst-Stams, W. A., Nillesen, W. M., Cormier-Daire, V., Houge, G., Foulds, N., van Dooren, M., Willemsen, M. H., Pfundt, R., Turner, A., Wilson, M., McGaughran, J., and 16 others. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J. Med. Genet. 46: 598-606, 2009. [PubMed: 19264732] [Full Text: https://doi.org/10.1136/jmg.2008.062950]
Maier, V. K., Feeney, C. M., Taylor, J. E., Creech, A. L., Qiao, J. W., Szanto, A., Das, P. P., Chevrier, N., Cifuentes-Rojas, C., Orkin, S. H., Carr, S. A., Jaffe, J. D., Mertins, P., Lee, J. T. Functional proteomic analysis of repressive histone methyltransferase complexes reveals ZNF518B as a G9A regulator. Molec. Cell. Proteomics 14: 1435-1446, 2015. [PubMed: 25680957] [Full Text: https://doi.org/10.1074/mcp.M114.044586]
Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M., Nakatani, Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296: 1132-1136, 2002. [PubMed: 12004135] [Full Text: https://doi.org/10.1126/science.1069861]
Ohno, H., Shinoda, K., Ohyama, K., Sharp, L. Z., Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504: 163-167, 2013. [PubMed: 24196706] [Full Text: https://doi.org/10.1038/nature12652]
Schaefer, A., Sampath, S. C., Intrator, A., Min, A., Gertler, T. S., Surmeier, D. J., Tarakhovsky, A., Greengard, P. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 64: 678-691, 2009. [PubMed: 20005824] [Full Text: https://doi.org/10.1016/j.neuron.2009.11.019]
Stumpf, A. M. Personal Communication. Baltimore, Md. 09/22/2020.
Ueda, J., Tachibana, M., Ikura, T., Shinkai, Y. Zinc finger protein Wiz links G9a/GLP histone methyltransferase to the co-repressor molecule CtBP. J. Biol. Chem. 281: 20120-20128, 2006. [PubMed: 16702210] [Full Text: https://doi.org/10.1074/jbc.M603087200]
Yuan, J., Chang, S.-Y., Yin, S.-G., Liu, Z.-Y., Cheng, X., Liu, X.-J., Jiang, Q., Gao, G., Lin, D.-Y., Kang, X.-L., Ye, S.-W., Chen, Z., Yin, J.-A., Hao, P., Jiang, L., Cai, S.-Q. Two conserved epigenetic regulators prevent healthy ageing. Nature 579: 118-122, 2020. [PubMed: 32103178] [Full Text: https://doi.org/10.1038/s41586-020-2037-y]