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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

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

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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

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

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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

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2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress

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

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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.

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