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PMID: 25752243 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 6 ·2015-03-10 ·Pages 6404

Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP

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.

MeSH Terms
Animals Autism Spectrum Disorder/genetics Chromatin Assembly and Disassembly/genetics DNA-Binding Proteins/genetics,metabolism Gene Expression Regulation, Developmental/genetics,physiology Gene Knockdown Techniques Gene Regulatory Networks/genetics Humans Mice Models, Neurological Nervous System/embryology,metabolism Neural Stem Cells/metabolism Transcription Factors/genetics,metabolism
Chemicals
CHD8 protein, human DNA-Binding Proteins Transcription Factors
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Cotney Justin ORCID
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.
Muhle Rebecca A
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.
Sanders Stephan J
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.
Liu Li
Department of Statistics, Carnegie Mellon University, Baker Hall 228B, Pittsburgh, Pennsylvania 15213, USA.
Willsey A Jeremy
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.
Niu Wei
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.
Liu Wenzhong
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.
Klei Lambertus
Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, USA.
Lei Jing
Department of Statistics, Carnegie Mellon University, Baker Hall 228B, Pittsburgh, Pennsylvania 15213, USA.
Yin Jun
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.
Reilly Steven K
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.
Tebbenkamp Andrew T ORCID
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.
Bichsel Candace
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.
Pletikos Mihovil
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.
Sestan Nenad
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.
Roeder Kathryn
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.
State Matthew W
Department of Psychiatry, University of California, 401 Parnassus Avenue, San Francisco, California 94143, USA.
Devlin Bernie
Department of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, USA.
Noonan James P
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.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms7404
Published
2015-03-10
Epub
2015-00-10
Pages
6404
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4355952
Subset
IM
Grants
NIMH NIH HHS · R37 MH057881 · United States
NIGMS NIH HHS · R01 GM094780 · United States
NIMH NIH HHS · R25 MH077823 · United States
NIGMS NIH HHS · GM094780 · United States
NIMH NIH HHS · R01 MH100028 · United States
NIMH NIH HHS · T32 MH018268 · United States
Canadian Institutes of Health Research · Canada
Howard Hughes Medical Institute · United States
NCATS NIH HHS · UL1 TR000142 · United States
NCI NIH HHS · P30 CA016359 · United States
Databases
GEO
GSE57369
External Links
PubMed source DOI: 10.1038/ncomms7404 PMC Full Text View journal details
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