Dataset Information

Duplication of autism-related gene Chd8 leads to behavioral hyperactivity and neurodevelopmental defects in mice [cortex]

ABSTRACT: Mutations in the gene encoding the chromodomain helicase DNA-binding protein 8 (CHD8) are strongly associated with autism spectrum disorder (ASD). Although duplications of the locus spanning CHD8 are also found in individuals with neurodevelopmental disorders, the role of CHD8 duplication in clinical phenotypes and the underlying mechanisms have remained unknown. Here we show that mice with Chd8 overexpression modeling human CHD8 duplication manifest growth retardation, microcephaly, and behavioral abnormalities including hyperactivity and reduced anxiety-like behavior. Chd8 overexpression results in alterations of transcription and chromatin accessibility of genes involved in neurogenesis that are associated with aberrant binding of CHD8 to enhancer regions and impairs differentiation of deep-layer neurons. Furthermore, genetic and pharmacological interventions rescue hyperactive behavior of Chd8 overexpression mice. Our results thus indicate that Chd8 overexpression mice recapitulate key features of CHD8 duplication syndrome, and they provide insight into cellular and molecular pathogenesis underlying neurodevelopmental disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE288732 | GEO | 2025/04/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Truncating mutations of CHD8, encoding a chromodomain helicase, and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA-seq) with genome-wide CHD8 binding (ChIP-seq). Suppressing CHD8 to levels comparable with loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8 binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (p = 1.01x10-9) and CHD8-bound genes (p = 4.34x10-3), which align with previously identified co-expression modules during fetal development. We also find an intriguing enrichment of cancer related gene-sets among CHD8-bound genes (p < 1.9x10-11). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. RNA-seq in NPCs treated with shRNAs targeting CHD8. For controls, NPCs were treated with shRNAs targeting GFP and LacZ. Infection and sequencing was carried out in two separate batches, with one GFP and one LacZ sample in each batch. All samples were sequenced in two technical replicates.

Dataset Information

Duplication of autism-related gene Chd8 leads to behavioral hyperactivity and neurodevelopmental defects in mice [cortex]

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets