CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

Proc Natl Acad Sci U S A
Authors
Keywords
Abstract

Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.

Year of Publication
2014
Journal
Proc Natl Acad Sci U S A
Volume
111
Issue
42
Pages
E4468-77
Date Published
2014 Oct 21
ISSN
1091-6490
URL
DOI
10.1073/pnas.1405266111
PubMed ID
25294932
PubMed Central ID
PMC4210312
Links
Grant list
MH095088 / MH / NIMH NIH HHS / United States
R01 HG004037 / HG / NHGRI NIH HHS / United States
R00 MH095867 / MH / NIMH NIH HHS / United States
GM061354 / GM / NIGMS NIH HHS / United States
K99 MH095867 / MH / NIMH NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
P30 CA014236 / CA / NCI NIH HHS / United States
MH095867 / MH / NIMH NIH HHS / United States
R01 MH095088 / MH / NIMH NIH HHS / United States