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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [RNA-seq]

ABSTRACT: The chromatin remodeler CHD8 is among the most frequently mutated genes in autism spectrum disorder (ASD). CHD8 has a dosage-sensitive role in ASD but when and how it becomes critical to human social function is unclear. Here, we conducted genomic analyses of heterozygous and homozygous Chd8 mouse embryonic stem cells and differentiated neural progenitors. We identify dosage-sensitive CHD8 transcriptional targets, sites of regulated accessibility, and an unexpected cooperation with SOX transcription factors. Collectively, our findings reveal that CHD8 negatively regulates expression of neuronal genes to maintain pluripotency and also during differentiation. Thus, CHD8 is essential for both the maintenance of pluripotency and neural differentiation, providing mechanistic insight into its function with potential implications for ASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE155217 | GEO | 2020/09/16

REPOSITORIES: GEO

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [ATAC-seq]

Project description:The chromatin remodeler CHD8 is among the most frequently mutated genes in autism spectrum disorder (ASD). CHD8 has a dosage-sensitive role in ASD but when and how it becomes critical to human social function is unclear. Here, we conducted genomic analyses of heterozygous and homozygous Chd8 mouse embryonic stem cells and differentiated neural progenitors. We identify dosage-sensitive CHD8 transcriptional targets, sites of regulated accessibility, and an unexpected cooperation with SOX transcription factors. Collectively, our findings reveal that CHD8 negatively regulates expression of neuronal genes to maintain pluripotency and also during differentiation. Thus, CHD8 is essential for both the maintenance of pluripotency and neural differentiation, providing mechanistic insight into its function with potential implications for ASD.

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation [ChIP-seq]

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The chromatin modifier CHD8 targets autism risk genes during human neurodevelopmentM-BM-

Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/M-NM-2-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development. Two biological replicates for each ChIP with appropriate Input control Four biological replicates for each condition in knockdown experiments (Ctrl construct, Chd8 target C, and Chd8 target G)

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CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation

Project description:CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation

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CHD8 Suppression Impacts on Histone H3 Lysine 36 Trimethylation and Alters RNA Alternative Splicing

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Project description:Mutations in the gene encoding the chromatin remodeler CHD8 are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have been involved in ASD pathogenesis, the underlying mechanisms of CHD8 in the regulation of cerebellar function has remained unknown, however. Here we show that the cerebellar granule neurons–specific deletion of Chd8 manifests reduced proliferation and differentiation of granule neuron progenitors, leading to cerebellar hypoplasia and motor coordination defects in mice. CHD8 was found to regulate the expression of neuronal genes and to be required for maturation of cerebellar granule neurons. Furthermore, we found that CHD8 is preferentially bound to promoter regions and is necessary for modulation of local chromatin accessibilities at promoter regions of active gene. Our results thus uncover a critical role for CHD8 in cerebellar development and have important implications for understanding the cerebellar contributions to ASD pathogenesis.

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