Abstract
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.
Highlights
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals
Using ChIP-seq with an antibody targeting an N-terminal epitope of CHD8 (Supplementary Fig. 2a,b), we identified CHD8-binding sites in H9-derived human NSCs and human midfetal brain at 16–19 post conception weeks (PCWs)
Many of the CHD8-binding sites in human midfetal brain were shared with human neural stem cells (hNSCs), identifying a set of genes that are targeted by CHD8 in both neurodevelopmental contexts (Fig. 1a)
Summary
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. Integration of CHD8-binding data into ASD risk models improves detection of risk genes These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development. Initial sequencing studies established that genes with multiple de novo loss of function mutations among unrelated persons with ASD are highly likely to confer risk for the disorder To date, nine such high-confidence[13] ASD risk genes have been identified: ANK2, CHD8, CUL3, DYRK1A, GRIN2B, KATNAL2, POGZ, SCN2A and TBR1. Nine such high-confidence[13] ASD risk genes have been identified: ANK2, CHD8, CUL3, DYRK1A, GRIN2B, KATNAL2, POGZ, SCN2A and TBR1 These genes encode proteins with a variety of functions, including chromatin modification and transcriptional regulation[14], suggesting molecular mechanisms perturbed in ASD. Owing to its chromatin remodelling activity, its association with other transcriptional regulators, and its increased expression during human midfetal development[15], CHD8 is a prime candidate for contributing to the organization of such networks by regulating other ASD risk genes
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