| Literature DB >> 28671691 |
Andrea L Gompers1,2, Linda Su-Feher1,2, Jacob Ellegood3, Nycole A Copping1,4, M Asrafuzzaman Riyadh5, Tyler W Stradleigh1,2, Michael C Pride1,4, Melanie D Schaffler1,4, A Ayanna Wade1,2, Rinaldo Catta-Preta1,2, Iva Zdilar1,2, Shreya Louis1,2, Gaurav Kaushik5, Brandon J Mannion6, Ingrid Plajzer-Frick6, Veena Afzal6, Axel Visel6,7,8, Len A Pennacchio6,7, Diane E Dickel6, Jason P Lerch3,9, Jacqueline N Crawley1,4, Konstantinos S Zarbalis5, Jill L Silverman1,4, Alex S Nord1,2.
Abstract
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.Entities:
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Year: 2017 PMID： 28671691 PMCID： PMC6008102 DOI： 10.1038/nn.4592
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884