@article {Gompers076158, author = {Andrea L. Gompers and Linda Su-Feher and Jacob Ellegood and Tyler W. Stradleigh and Iva Zdilar and Nycole A. Copping and Michael C. Pride and Melanie D. Schaffler and M. Asrafuzzaman Riyadh and Gaurav Kaushik and Brandon Mannion and Ingrid Plajzer-Frick and Veena Afzal and Axel Visel and Len A. Pennacchio and Diane Dickel and Jason P. Lerch and Jacqueline N. Crawley and Konstantinos S. Zarbalis and Jill L. Silverman and Alex S. Nord}, title = {Heterozygous mutation to Chd8 causes macrocephaly and widespread alteration of neurodevelopmental transcriptional networks in mouse}, elocation-id = {076158}, year = {2016}, doi = {10.1101/076158}, publisher = {Cold Spring Harbor Laboratory}, abstract = {The chromatin remodeling gene CHD8 represents a central node in early neurodevelopmental gene networks implicated in autism. We examined the impact of heterozygous germline Chd8 mutation on neurodevelopment in mice. Network analysis of neurodevelopmental gene expression revealed subtle yet strongly significant widespread transcriptional changes in Chd8+/- mice across autism-relevant networks from neurogenesis to synapse function. Chd8+/- expression signatures included enrichment of RNA processing genes and a Chd8-regulated module featuring altered transcription of chromatin remodeling, splicing, and cell cycle genes. Chd8+/- mice exhibited increased proliferation during brain development and neonatal increase in cortical length and volume. Structural MRI confirmed regional brain volume increase in adult Chd8+/- mice, consistent with clinical macrocephaly. Adult Chd8+/- mice displayed normal social interactions, and repetitive behaviors were not evident. Our results show that Chd8+/- mice exhibit neurodevelopmental changes paralleling CHD8+/- humans and show that Chd8 is a global genomic regulator of pathways disrupted in neurodevelopmental disorders.}, URL = {https://www.biorxiv.org/content/early/2016/09/20/076158}, eprint = {https://www.biorxiv.org/content/early/2016/09/20/076158.full.pdf}, journal = {bioRxiv} }