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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE89010 | GEO | 2018/03/07

SECONDARY ACCESSION(S): PRJNA350166

REPOSITORIES: GEO

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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

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

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2023-01-30 | PXD030265 | Pride

EHMT1 gene truncation in HEK293 cells recapitulates Kleefstra Syndrome disease phenotype

Project description:Haploinsufficiency of the Euchromatin histone methyltransferase 1 (EHMT1) gene leads to Kleefstra Syndrome, a rare disease characterised by moderate to severe developmental delay/intellectual disability, childhood hypotonia and distinct facial features, comprising microcephaly. This study examines the genetic variant EHMT1_Ter (p.[Tyr1148=];[Tyr1148Leufs*9]) in HEK293 cells.

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

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2021-06-09 | GSE162327 | GEO

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

Expression data from pre-iPSCs with a control, histone methyltransferase or Cbx3 (HP1g) knockdown

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2013-06-05 | E-GEOD-44084 | biostudies-arrayexpress

CRISPR gene editing and inducible pluripotent stem cell neuronal disease modelling for rare disease diagnosis: EMHM1 genetic variant analysis in Kleefstra Syndrome

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2021-06-23 | GSE178646 | GEO

EHMT1 gene truncation in HEK293 cells recapitulates Kleefstra Syndrome disease phenotype

Project description:EHMT1 gene truncation in HEK293 cells recapitulates Kleefstra Syndrome disease phenotype

| PRJNA661188 | 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.

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