CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors
Abstract
Truncating mutation of chromodomain helicase DNA-binding protein 8 (CHD8) represents one of the strongest known risk factors for autism spectrum disorder (ASD). We mimicked the effects of such heterozygous loss-of-function mutations in neural progenitor cells and integrated RNA sequencing with genome-wide delineation of CHD8 binding. Our results reveal that the molecular mechanism by which CHD8 alters neurodevelopmental pathways may involve both direct and indirect effects, the latter involving down-regulation following CHD8 suppression. We also find that chd8 suppression in zebrafish results in macrocephaly, consistent with observations in patients harboring loss-of-function mutations. We show that reduced expression of CHD8 impacts a variety of other functionally distinct ASD-associated genes, suggesting that the diverse functions of ASD risk factors may constitute multiple means of triggering a smaller number of final common pathways.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- October 2014
- DOI:
- 10.1073/pnas.1405266111
- Bibcode:
- 2014PNAS..111E4468S