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

Aarathi Sugathan, Marta Biagioli, Christelle Golzio, Serkan Erdin, Ian Blumenthal, Poornima Manavalan, Ashok Ragavendran, Harrison Brand, Diane Lucente, Judith Miles, Steven D. Sheridan, Alexei Stortchevoi, Manolis Kellis, Stephen J. Haggarty, Elias Nicholas Katsanis, James F. Gusella, Michael E. Talkowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

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% ofwhich 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.

Original languageEnglish (US)
Pages (from-to)E4468-E4477
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number42
DOIs
StatePublished - Oct 21 2014

Keywords

  • Autism
  • CHD8
  • ChIP-seq
  • NPCs
  • RNA-seq

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors'. Together they form a unique fingerprint.

Cite this