Epigenomic Mechanisms Underlying Pathology in Chd8 Haploinsufficiency

Background: Exome sequencing studies of patients with autism spectrum disorder (ASD) have identified de novo mutations in CHD8. CHD8 haploinsufficiency is proposed to drive neurodevelopmental pathology via genome-wide changes in chromatin state and gene expression. However, the biological processes and underlying regulatory mechanisms negatively impacted during neurodevelopment by reduced CHD8 dosage remain unknown. Mapping these changes may give insight into ASD pathophysiology.

Objectives: We used a mouse model harboring a germline loss-of-function mutation in Chd8 to study the role of Chd8 and chromatin remodeling in neurodevelopment through genomic characterization.

Methods: Bulk forebrain was dissected from Chd8^+/- and wildtype littermates at post-conception days 12.5, 14.5, 17.5, 21, and ~77. We used RNA-seq and ChIP-seq to map the transcriptional and genomic impact of Chd8 haploinsufficiency during development.

Results: Transcriptional profiling of Chd8^+/- mice revealed widespread transcriptional changes throughout development involving genes important for RNA processing and chromatin remodeling as well as genes previously implicated in studies of genetic contributions to ASD. Epigenomic profiling of Chd8 binding provides evidence that it directly regulates expression of differentially expressed genes, including RNA processing, chromatin remodeling, and ASD-relevant genes. Further analysis shows strong Chd8 binding to genes with decreasing expression over neurodevelopment, suggesting typical Chd8 expression is required for transcriptional activation during brain development.

Conclusions: These results reveal pathophysiology associated with single copy loss-of-function mutations of chromatin remodeling genes, providing insight into one of the most intriguing findings from large-scale ASD genetic studies.