The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment

TLDR

Chromatin modifiers, including recurrent de novo loss‑of‑function mutations, are implicated in ASD, and ASD risk genes are co‑expressed in human midfetal cortex, indicating convergence in specific regulatory networks during neurodevelopment. The study aims to identify genes targeted by CHD8 in human midfetal brain, human neural stem cells, and embryonic mouse cortex to elucidate ASD‑related regulatory networks. The authors mapped CHD8 target genes in human midfetal brain, hNSCs, and embryonic mouse cortex. CHD8 targets are enriched for other ASD risk genes and converge in ASD‑associated co‑expression networks in human midfetal cortex; knockdown of CHD8 in hNSCs dysregulates directly targeted ASD risk genes; incorporating CHD8‑binding data into risk models improves detection of risk genes, indicating that loss of CHD8 perturbs an ancient regulatory network during human brain development.

Abstract

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.