Novel CHD8 genomic targets identified in fetal mouse brain by in vivo Targeted DamID

ABSTRACT

Genetic studies of autism spectrum disorder (ASD) have revealed a causal role for mutations in chromatin remodeling genes. Chromodomain helicase DNA binding protein 8 (CHD8) encodes a chromatin remodeler with one of the highest de novo mutation rates in sporadic ASD. However, the relationship between CHD8 genomic function and autism-relevant biology remains poorly elucidated. CHD8 binding studies have relied on Chromatin Immunoprecipitation followed by sequencing (ChIP-seq), however, these datasets exhibit significant variability. ChIP-seq has technical limitations in the context of weak or indirect protein-DNA interactions or when high-performance antibodies are unavailable. Thus, complementary approaches are needed overall, and, specifically, to establish CHD8 genomic targets and regulatory function. Here we used Targeted DamID in utero to characterize CHD8 binding in developing embryonic mouse cortex. CHD8 Targeted DamID followed by sequencing (CHD8 TaDa-seq) revealed binding at previously identified targets as well as loci sensitive to Chd8 haploinsufficiency. CHD8 TaDa-seq highlighted CHD8 binding distal to a subset of genes specific to neurodevelopment and neuronal function. These studies establish TaDa-seq as a useful alternative for mapping protein-DNA interactions in vivo and provide insights into the relationship between chromatin remodeling by CHD8 and autism-relevant pathophysiology associated with CHD8 mutations.