Hot Publication - Devlin & Colleagues
The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment
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 and Noonan JP.
Nature Communications, 6:6404, 2015
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.
Professor Bernie Devlin, in collaboration with colleagues at Yale, the University of California at San Francisco and Carnegie Mellon University, identified genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex to elucidate such networks. 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.
The investigators found that integration of CHD8-binding data into ASD risk models improves detection of risk genes. The results of this study also suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.
Bernie Devlin, PhD and Lambertus Klei, PhD (Department of Psychiatry, University of Pittsburgh)
Justin Cotney, PhD, Candace Bichsel, PhD, Wenzhong Liu, PhD, Rebecca A. Muhle, MD, Wei Niu, PhD, James P. Noonan, PhD, Mihovil Pletikos, MD, Steven K. Reilly, PhD, Nenad Sestan, MD, PhD, Andrew T. Tebbenkamp PhD, A. Jeremy Willsey, BSc, MPhil and Jun Yin, PhD (Departments of Genetics and Neurobiology, Child Study Center and Kavli Institute for Neuroscience, Yale School of Medicine)
Stephan J. Sanders, PhD and Matthew W. State, MD, PhD (Department of Psychiatry, University of California at San Francisco)
Li Liu, PhD, MPhil, Jing Lei, PhD and Kathryn Roeder, PhD (Department of Statistics, Carnegie Mellon University)