Expression of Data from EHMT1 siRNA transfected HeLa cell treated with TNF
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: chee-kwee ea
PROVIDER: E-GEOD-39744 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:We used microarrays to detail the global programme of gene expression to identify TNF-induced genes that are negatively regulated by EHMT1 Transcriptional homeostasis relies on the balance between positive and negative regulation of gene transcription. Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. Here, we report that a euchromatic H3K9 methyltransferase, EHTM1, functions as a negative regulator in both the NF-κB- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-κB target genes. Moreover, EHMT1 interacts with p50 and, surprisingly, p50 appears to repress the expression of type I interferon genes and genes activated by type I interferons by recruiting EHMT1 to catalyze H3K9 methylation at their promoter regions. Silencing the expression of EHMT1 by RNA interference enhances expression of a subset NF-κB regulated genes, augments interferon production and augments antiviral immunity.
2012-07-31 | GSE39744 | GEO
Project description:EHMT1 (also known as GLP) is a multifunctional protein, best known for its role as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with EHMT2 (also known as G9A). Here, we investigated the role of EHMT1 in the oocyte in comparison to EHMT2 using oocyte-specific conditional knockout mouse models (Ehmt2 cKO, Ehmt1cKO, Ehmt1/2 cDKO), with ablation from the early phase of oocyte growth. Loss of EHMT1 in Ehmt1 cKO and Ehmt1/2 cDKO oocytes recapitulated meiotic defects observed in the Ehmt2 cKO; however, there was a significant impairment in oocyte maturation and developmental competence in Ehmt1 cKO and Ehmt1/2 cDKO oocytes beyond that observed in the Ehmt2cKO. Consequently, loss of EHMT1 in oogenesis results, upon fertilization, in mid-gestation embryonic lethality. To identify H3K9 methylation and other meaningful biological changes in each mutant to explore the molecular functions of EHMT1 and EHMT2, we performed immunofluorescence imaging, multi-omics sequencing, and mass spectrometry (MS)–based proteome analyses in cKO oocytes. Although H3K9me1 was depleted only upon loss of EHMT1, H3K9me2 was decreased, and H3K9me2-enriched domains were eliminated equally upon loss of EHMT1 or EHMT2. Furthermore, there were more significant changes in the transcriptome, DNA methylome, and proteome in Ehmt1/2 cDKO than Ehmt2 cKO oocytes, withtranscriptional derepression leading to increased protein abundance and local changes in genic DNA methylation in Ehmt1/2 cDKO oocytes. Together, our findings suggest that EHMT1 contributes to local transcriptional repression in the oocyte, partially independent of EHMT2, and is critical for oogenesis and oocyte developmental competence
2023-01-30 | PXD030265 | Pride
Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.
2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress
Project description:EHMT1 haploinsufficiency causes Kleefstra syndrome (KS), a complex disorder of developmental delay and intellectual disability. EHMT1 encodes a lysine methyltransferase GLP and regulates histone H3 lysine 9 dimethylation (H3K9me2). Ehmt1 heterozygous mutant (Ehmt1∆/+) mice show KS-like abnormal behavioral phenotypes. Here, we examined the reversibility of decreased H3K9me2 by postnatal supply of GLP in post-mitotic neuron of Ehmt1∆/+ mice brain. For this purpose, we generated the mice harboring inducible Ehmt1 cDNA with CamKII-creER (Ehmt1 iTG-neuron mice) in Ehmt1∆/+ background. These mice expressed exogenous Ehmt1 in post-mitotic neuron upon Tamoxifen treatment. Using these mice, we sorted out NeuN+ cells from cortical region and performed Histone H3 K9-dimethyation ChIP analysis. Here we showed that Ehmt1 haploinsufficiency induces global reduction of euchromatic H3K9me2 especially in the euchromatic region of brain and that postnatal supply of GLP can reverse the diminished H3K9me2 phenotype, even in a postmitotic situation.
2021-06-09 | GSE162327 | GEO
Project description:The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. The transcription factors nuclear factor kB (NF-kB) and the interferon (IFN) regulatory factors (IRFs) bind to the kB site and the interferon response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-kB p50 homodimer (p50:p50) as a regulator of IRF responses. First, unbiased genome-wide expression analysis revealed that p50 repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences, which was substantiated by biochemical and structural analyses. Second, mathematical modeling predicted that p50:p50 might enforce the stimulus-specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-b was rendered stimulus-specific by the binding of p50:p50 to the G-IRE–containing IFNb enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-b in response to bacterial DNA sensed by Toll-like receptor 9. This role for NF-kB p50 in enforcing the specificity of the cellular response to pathogens by binding to a previously uncharacterized subset of IRE sequences alters our understanding of how the NF-kB and IRF signaling systems cooperate to regulate antimicrobial immunity. [BMDM]: Total RNA extracted from wt, p50-/- or ifnar-/- bone marrow derived macrophages (BMDMs) were subjected to stimulation with LPS, CpG or IFNb [MEF]: Total RNA extracted from wt or p50KO primary mouse embryonic fibroblasts were subjected to stimulation with LPS or IFNb
2011-03-01 | E-GEOD-27112 | biostudies-arrayexpress
Project description:The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. The transcription factors nuclear factor kB (NF-kB) and the interferon (IFN) regulatory factors (IRFs) bind to the kB site and the interferon response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-kB p50 homodimer (p50:p50) as a regulator of IRF responses. First, unbiased genome-wide expression analysis revealed that p50 repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences, which was substantiated by biochemical and structural analyses. Second, mathematical modeling predicted that p50:p50 might enforce the stimulus-specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-b was rendered stimulus-specific by the binding of p50:p50 to the G-IRE–containing IFNb enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-b in response to bacterial DNA sensed by Toll-like receptor 9. This role for NF-kB p50 in enforcing the specificity of the cellular response to pathogens by binding to a previously uncharacterized subset of IRE sequences alters our understanding of how the NF-kB and IRF signaling systems cooperate to regulate antimicrobial immunity.
2011-03-01 | GSE27112 | GEO
Project description:Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activityregulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
2020-07-29 | GSE155291 | GEO
Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma, wherein the malignant tumors arise from the myoblast like cells due to the perturbations in growth and differentiation. Alveolar rhabdomyosarcoma (ARMS) is one of the two major histological subtypes which exhibits high metastatic potential and tumor recurrence culminating in poor prognosis. In the recent past, understanding the epigenetic modifications in these tumors with less genetic alterations has shed light on the process of tumor pathogenesis and development of potential epi-drugs for the effective treatment strategies. Epigenetic regulator, Euchromatin histone lysine methyltransferase 1 (EHMT1)/G9A-like protein (GLP) and its homolog Euchromatin histone lysine methyltransferase 1 (EHMT2)/G9A has been shown to promote proliferation and inhibit differentiation in the mouse myoblast cells, independently. Also, previous study from our lab reported the overexpression of EHMT2 and molecular mechanism associated with the oncogenic phenotype in ARMS. However, expression pattern and functional role of EHMT1 in ARMS is unknown. Herein, we investigated the role of EHMT1 in ARMS. Our preliminary data indicated the overexpression of EHMT1 and the associated oncogenic phenotypes in ARMS. Although EHMT1 has shown to be upregulated and correlated with the increased disease severity in several cancers including gastric, esophagus, squamous cell carcinoma, ovarian and breast cancer, the mechanism involved in the EHMT1 mediated tumorigenesis was unclear. Therefore, through our current study we aimed to understand the expression pattern and the mechanism through which EHMT1 regulated cancer phenotypes in ARMS, for this we performed whole transcriptomic analysis in ARMS cell lines upon EHMT1 knockdown for the first time. In addition, we also compared the expression levels of EHMT1 between Human skeletal muscle myoblasts (HSMM) and ARMS patient samples (obtained from St Jude cloud database).
2021-12-08 | GSE179049 | GEO
Project description:The methylation of histone 3 at lysine 9 (H3K9) is widely regarded as a major roadblock for cellular reprogramming and interference with associated methyltransferases such as EHMT1 and EHMT2 (also known as GLP and G9A) facilitates the derivation of induced pluripotent stem cells (iPSCs). In addition, activation of demethylases by ascorbic acid (AA) has become a common approach to facilitate the extensive epigenetic remodeling required for iPSC formation. The functional interaction between the H3K9 methylation machinery and AA-stimulated enzymes, and consequences of interfering with these pathways, remain insufficiently explored. Here, we show that reduction of EHMT1/2 activity paradoxically counteracts iPSC formation in an optimized reprogramming system in the presence of AA. At the cellular and molecular level, EHMT1/2 activity is required for efficient downregulation of somatic genes and transition into an epithelial state. Genetic interference with the demethylase KDM3B partially rescues the adverse effect of EHMT1/2 inhibition on iPSC formation. Transient inhibition of EHMT1/2 during reprogramming yields iPSCs that fail to efficiently give rise to viable mice, suggesting persistent molecular defects in these cells. Together, our observations document a more nuanced function of H3K9 methyltransferases during iPSC formation and suggest that the balancing of AA-stimulated enzymes by EHMT1/2 is required for efficient and error-free reprogramming to pluripotency.
2020-09-28 | GSE130490 | GEO
Project description:Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of aging and neurodegeneration. Here we found that, in the late-stage familial Alzheimer’s disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9Me2) and euchromatic histone methyltransferases, EHMT1 and EHMT2 (H3K9Me2 catalyzer), were significantly elevated in the prefrontal cortex (PFC) region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9Me2 at the promoter region of glutamate receptors was increased in PFC of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in PFC and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9Me2 enrichment at genes involved in neuronal signaling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.
2019-01-30 | GSE125850 | GEO