RT Journal Article SR Electronic T1 Heterozygous mutation to Chd8 causes macrocephaly and widespread alteration of neurodevelopmental transcriptional networks in mouse JF bioRxiv FD Cold Spring Harbor Laboratory SP 076158 DO 10.1101/076158 A1 Andrea L. Gompers A1 Linda Su-Feher A1 Jacob Ellegood A1 Tyler W. Stradleigh A1 Iva Zdilar A1 Nycole A. Copping A1 Michael C. Pride A1 Melanie D. Schaffler A1 M. Asrafuzzaman Riyadh A1 Gaurav Kaushik A1 Brandon Mannion A1 Ingrid Plajzer-Frick A1 Veena Afzal A1 Axel Visel A1 Len A. Pennacchio A1 Diane Dickel A1 Jason P. Lerch A1 Jacqueline N. Crawley A1 Konstantinos S. Zarbalis A1 Jill L. Silverman A1 Alex S. Nord YR 2016 UL http://biorxiv.org/content/early/2016/09/20/076158.abstract AB 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.