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Title: Germline Chd8 haploinsufficiency alters brain development in mouse

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. In this paper, 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. Finally, this integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.
Authors:
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  1. Univ. of California, Davis, CA (United States). Dept. of Psychiatry and Behavioral Sciences. Dept. of Neurobiology, Physiology and Behavior
  2. The Hospital for Sick Children, Toronto, ON (Canada). Mouse Imaging Centre
  3. Univ. of California, Davis, CA (United States). Dept. of Psychiatry and Behavioral Sciences. MIND Inst. School of Medicine
  4. Univ. of California, Davis, Sacramento, CA (United States). Dept. of Pathology and Laboratory Medicine. Shriners Hospitals for Children. Inst. for Pediatric Regenerative Medicine
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Functional Genomics Dept.
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Functional Genomics Dept.; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Univ. of California, Merced, CA (United States). School of Natural Sciences
  7. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Functional Genomics Dept.; USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)
  8. The Hospital for Sick Children, Toronto, ON (Canada). Mouse Imaging Centre; Univ. of Toronto, ON (Canada). Dept. of Medical Biophysics
Publication Date:
Grant/Contract Number:
AC02-05CH11231; U54 HD079125; NIGMS R35 GM119831; T32-GM008799; T32-GM007377; R24HL123879; U01DE024427; R01HG003988; U54HG006997; UM1HL098166
Type:
Accepted Manuscript
Journal Name:
Nature Neuroscience
Additional Journal Information:
Journal Volume: 20; Journal Issue: 8; Journal ID: ISSN 1097-6256
Publisher:
Springer Nature
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Davis, CA (United States); The Hospital for Sick Children, Toronto, ON (Canada)
Sponsoring Org:
USDOE; Univ. of California, Davis (United States); National Inst. of Health (NIH) (United States); National Council for Scientific and Technological Development (CNPq) (Brazil); Canadian Inst. for Health Research (CIHR)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; autism spectrum disorders; functional genomics; neuronal development
OSTI Identifier:
1436635