Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Post-natal supply of GLP/Ehmt1 reverses Histone H3K9 dimethylation in cortical neuron isolated from adult Ehmt1∆/+ mice brain

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE162327 | GEO | 2021/06/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Derepression of inflammation-related genes link to microglia activation and neural maturation defect in a mouse model of Kleefstra Syndrome

Project description:Kleefstra syndrome (KS, also known as 9q.34.3 deletion syndrome) is a rare genetic disorder characterized by a developmental delay, abnormal behaviors and autism-like features. This syndrome is caused by haplo-insufficiency of the euchromatin histone methyltransferase 1 gene (EHMT1/GLP/KDM1D). This gene product, GLP is a methyltransferase responsible for mono- and di-methylation of lysine 9 on histone H3 N-terminal tail, which modulates epigenetic information. Ehmt1 heterozygous mutant (Ehmt1∆/+) mice show KS-like abnormal behavioral phenotypes and utilized as KS model mice. Here, we isolated nuclei from adult Ehmt1∆/+ mice cortex and analysed gene expression precisely by single nucleus RNA-seq analysis. It showed that many genes were up or down regulated in different cell types of Ehmt1∆/+ mice brain. Among them, inflammation associating genes are up-regulated in Ehmt1∆/+ mice neuronal cells. And this up-regulation was reversed by postnatal supply of GLP in post-mitotic neuron of Ehmt1∆/+ mice brain.

2021-06-11 | GSE162934 | GEO

Multi-omics analyses demonstrate a critical role for EHMT1 methyltransferase in transcriptionalrepression during oogenesis

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

Identification of proteins stably associated with G9a/GLP (EHMT2/EHMT1) complex of histone methyltransferases

Project description:G9a (EHMT2) and the G9a-like protein GLP (EHMT1) form a stable G9a/GLP heterodimer in embryonic stem cells and function cooperatively to establish and maintain the abundant repressive H3K9me2 modification, in addition to modifying several non-histone proteins. The G9a-dependent H3K9me2 is implicated in lineage-specific gene silencing and covers large chromosomal domains. While the mechanism of H3K9me2maintenance by G9a/GLP is known, how new patterns of this modification are established is not well understood. With this in mind, we used FLAG affinity purification of G9a under two different stringency conditions (150 and 300 mM NaCl) coupled with mass spectrometry to identify proteins stably associated with G9a/GLP, which could serve as potential recruiters of the complex to unmodified chromatin.

2016-03-16 | PXD003466 | Pride

Post-natal supply of GLP/Ehmt1 reverses Histone H3K9 dimethylation in cortical neuron isolated from adult Ehmt1∆/+ mice brain

Project description:Post-natal supply of GLP/Ehmt1 reverses Histone H3K9 dimethylation in cortical neuron isolated from adult Ehmt1∆/+ mice brain

| PRJNA681530 | ENA

Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease

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

Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

Project description:Homeostatic plasticity, a form of synaptic plasticity, maintains the fine balance between overall excitation and inhibition in developing and mature neuronal networks. Although the synaptic mechanisms of homeostatic plasticity are well characterized, the associated transcriptional program remains poorly understood. We show that the Kleefstra syndrome-associated protein, EHMT1, plays a critical and cell-autonomous role in synaptic scaling by responding to attenuated neuronal firing or sensory drive. Chronic activity deprivation increased the amount of neuronal dimethylated H3 at lysine 9 (H3K9me2), the catalytic product of EHMT1 and an epigenetic marker for gene repression. Genetic knockdown and pharmacological blockade of EHMT1 or EHMT2 prevented the increase of H3K9me2 and synaptic scaling up. Furthermore, BDNF repression was preceded by EHMT1/2-mediated H3K9me2 deposition at the Bdnf promoter during synaptic scaling up, both in vivo or in vivo. These findings suggest that changes in chromatin state through H3K9me2 governs a repressive program to achieve synaptic scaling. 12 samples (4 conditions in biological triplicate), 3 wt, 3 wt tetradotoxin treated, 3 k.d., 3 k.d. tetradotoxin treated

2016-06-30 | E-GEOD-68960 | biostudies-arrayexpress

Histone methylation by the Kleefstra Syndrome protein EHMT1 mediates homeostatic synaptic scaling.

2016-06-30 | GSE68960 | GEO

Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

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

Expression of Data from EHMT1 siRNA transfected HeLa cell treated with TNF

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-?B- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-?B 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-?B regulated genes, augments interferon production and augments antiviral immunity. HeLa cells were double-transfected with control or EHMT1 specific siRNAs. The cells were then treated with or without TNFa for 2 hours followed by RNA extraction and hybridization on Affymetrix microarrays.

2012-07-30 | E-GEOD-39744 | biostudies-arrayexpress

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome

Project description:Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/- adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/- mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/- mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/- mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.

2018-03-07 | GSE89010 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data