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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [RNA-seq]

ABSTRACT: We performed RNAseq experiments to examine genome-wide transcriptional changes in PFC of Shank3 +/∆C mice with or without GSK-LSD1 treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE193380 | GEO | 2022/01/13

REPOSITORIES: GEO

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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [ChIP-seq]

Project description:We performed chromatin immunoprecipitation sequencing (ChIPseq) to profile genome-wide occupancy of H3K4me2 in PFC from WT mice and Shank3 +/∆C Tau mice.

2022-01-13 | GSE193404 | GEO

Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.

Project description:Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.

| S-EPMC9477974 | biostudies-literature

Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models

Project description:To determine whether histone deacetylase (HDAC) inhibition has genome-wide effects on gene expression, we used RNA sequencing to analyze the mRNA profile in prefrontal cortex (PFC) of wild-type (WT) and Shank3-deficient (Shank3+/ΔC) mice treated with romidespin or saline control. We mapped the sequences to 24,420 mouse genes. Compared to WT, 365 genes in saline-treated Shank3+/ΔC mice showed a change in expression values of at least 1.2 fold and p ≤ 0.01 (213 downregulated, 152 upregulated). In romidepsin-treated Shank3+/ΔC mice, ~88% of the downregulated genes (n=187 genes) were normalized to control values. Further analysis of the romidepsin-restored genes revealed enrichment in actin cytoskeleton-mediated transport, signal transduction pathways, and developmental processes.

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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice

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.

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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-01-13 | GSE193405 | GEO

Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models

Project description:Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models

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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [RNA-seq]

Project description:Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [RNA-seq]

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Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [ChIP-seq]

Project description:Targeting Histone Demethylase LSD1 for Treatment of Deficits in Autism Mouse Models [ChIP-seq]

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Human small intestinal organoids grown with a specific protocol to enrich for Paneth cells were treated with an inhbitor (GSK-LSD1) for the epigenetic modulator LSD1.

Project description:To assess the role of LSD1 in human intestinal epithelium, human small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. The organoids were grown with specific conditions where Paneth cells are present in the organoids as similar experiments in mice show that Paneth cells disappear upon GSK-LSD1 treatment. Similar to mouse intestinal organoids, Paneth cells dissappear upon GSK-LSD1 treatment. Furthermore, we used these gene set enrichment analysis on these microarray data to show that these human intestinal organoids have a similar phenotype as mice epithelium without LSD1.

2020-11-16 | E-MTAB-7863 | biostudies-arrayexpress

RNA-seq of small intestinal organoids treated with an inhibitor for the epigenetic modifier LSD1

Project description:To assess the role of LSD1 in mice small intestinal epithelium, small intestinal organoids were treated with an inhibitor for LSD1 (GSK-LSD1) and compared to untreated organoids. Similar to intestinal epithelium from mice with an intestinal epithelium specific LSD1-KO, paneth cells dissappear upon GSK-LSD1 treatment. We used these sequencing data to show that these small intestinal organoids have a similar phenotype as mice epithelium without LSD1.

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