Germline Chd8 haploinsufficiency alters brain development in mouse

• Published in: Nature neuroscience Vol. 20; no. 8; pp. 1062 - 1073
• Main Authors: Gompers, Andrea L, Su-Feher, Linda, Ellegood, Jacob, Copping, Nycole A, Riyadh, M Asrafuzzaman, Stradleigh, Tyler W, Pride, Michael C, Schaffler, Melanie D, Wade, A Ayanna, Catta-Preta, Rinaldo, Zdilar, Iva, Louis, Shreya, Kaushik, Gaurav, Mannion, Brandon J, Plajzer-Frick, Ingrid, Afzal, Veena, Visel, Axel, Pennacchio, Len A, Dickel, Diane E, Lerch, Jason P, Crawley, Jacqueline N, Zarbalis, Konstantinos S, Silverman, Jill L, Nord, Alex S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2017; Nature Publishing Group; Springer Nature
• Subjects: 13/51; 14/19; 38/23; 38/77; 45/15; 45/88; 45/91; 49/1; 49/22; 49/39; 49/90; 59/57; 60 APPLIED LIFE SCIENCES; 631/208/191; 631/208/366/1373; 631/378/2571/1696; 64/60; 82/29; Animal Genetics and Genomics; Animals; Autism; autism spectrum disorders; Behavioral Sciences; Biological Techniques; Biomedicine; Brain; Brain - metabolism; Cell Cycle Proteins - genetics; Chromatin; Chromatin - metabolism; Chromatin remodeling; Cognitive ability; Developmental neurology; DNA-Binding Proteins - genetics; Frameshift mutation; functional genomics; Gene expression; Gene Expression Regulation, Developmental - genetics; Gene Regulatory Networks - genetics; Genetic aspects; Haploinsufficiency; Haploinsufficiency - genetics; Mice; Mice, Transgenic; Mutation; Mutation - genetics; Network analysis; Neurobiology; Neurodevelopmental disorders; Neurogenesis; neuronal development; Neurosciences; Perturbation methods; Phenotype; Physiological aspects; Ribonucleic acid; RNA; RNA processing; Social factors; Social interactions; Splicing; Transcription; Transcription Factors - genetics; United States
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.4592

Strong genetic evidence points to a significant role for heterozygous mutations to general chromatin remodeling factors, such as CHD8, in autism. Gompers et al . combine genomic, neuroanatomical and behavioral approaches to present an initial integrative picture of transcriptional mechanisms and widespread impacts of Chd8 haploinsufficiency across brain development in mice. The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 +/ del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 +/ del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8 +/ del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8 +/ del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.