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Nat Commun. 2015 Mar 10;6:6404. doi: 10.1038/ncomms7404.

The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

Author information

1
1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA.
2
1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA [3] Child Study Center, Yale School of Medicine, 230S. Frontage Road, New Haven, Connecticut 06519, USA.
3
1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Department of Psychiatry, University of California, 401 Parnassus Avenue, San Francisco, California 94143, USA.
4
Department of Statistics, Carnegie Mellon University, Baker Hall 228B, Pittsburgh, Pennsylvania 15213, USA.
5
Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, USA.
6
1] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA [2] Department of Neurobiology, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06510, USA.
7
1] Department of Statistics, Carnegie Mellon University, Baker Hall 228B, Pittsburgh, Pennsylvania 15213, USA [2] Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, 7401 Gates-Hillman Center, 5000 Forbes Avenue, Pittsburgh, Pennsylvania 15213, USA.
8
Department of Psychiatry, University of California, 401 Parnassus Avenue, San Francisco, California 94143, USA.

Abstract

Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

PMID:
25752243
PMCID:
PMC4355952
DOI:
10.1038/ncomms7404
[Indexed for MEDLINE]
Free PMC Article
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