The Autism-associated Chromatin Modifier CHD8 Regulates Other Autism Risk Genes During Human Neurodevelopment

Justin Cotney; Rebecca A Muhle; Stephan J Sanders; Li Liu; A Jeremy Willsey; Wei Niu; Wenzhong Liu; Lambertus Klei; Jing Lei; Jun Yin; Steven K Reilly; Andrew T Tebbenkamp; Candace Bichsel; Mihovil Pletikos; Nenad Sestan; Kathryn Roeder; Matthew W State; Bernie Devlin; James P Noonan;

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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.

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