Discovering Gene Regulatory Networks in Early Human Brain Development That Contribute to Autism Spectrum Disorder

Autism spectrum disorder (ASD) originates during early brain development and imposes a lifelong burden on affected individuals and their families. Insight into the specific molecular processes and cell types perturbed in ASD remains limited, which has hindered the design of effective treatments. However, recent studies have begun to reveal genetic factors contributing to ASD risk, providing an avenue to understand its biological basis. These efforts have identified multiple ASD risk genes with deleterious, heterozygous de novo mutations in affected individuals. Many of these genes encode chromatin modifiers and converge in gene coexpression networks in mid fetal human cortex. These findings suggest that disruption of gene regulatory networks in the prenatal human brain contributes to autism pathology. The ASD risk gene with the strongest association yet detected in whole exome surveys is the chromodomain helicase CHD8. The goal of this proposal is to identify the target networks of ASD risk genes controlled by CHD8, thereby revealing common regulatory pathways underlying ASD progression. In preliminary studies, we have mapped genes regulated by CHD8 during mouse and human neurodevelopment. We found that other ASD risk genes are overrepresented among CHD8 targets, and that ASD risk genes were dysregulated by loss of CHD8. We will build on this work by elucidating regulatory networks for multiple ASD-associated chromatin modifiers in three cell types of the developing cortex that have been implicated in ASD: neuronal stem cells, deep layer excitatory projection neurons, and upper layer excitatory projection neurons. In complementary studies, we will use mouse models to determine the celltype specific effects of CHD8 loss-of-function on regulatory networks during cortical development. Together, our findings will reveal common regulatory pathways underlying ASD, providing fundamental biological insights into the origins of the disorder.