Germline Chd8 haploinsufficiency alters brain development in mouse

Andrea L. Gompers, Linda Su-Feher, Jacob Ellegood, Nycole A. Copping, M. Asrafuzzaman Riyadh, Tyler W. Stradleigh, Michael C. Pride, Melanie D. Schaffler, A. Ayanna Wade, Rinaldo Catta-Preta, Iva Zdilar, Shreya Louis, Gaurav Kaushik, Brandon J. Mannion, Ingrid Plajzer-Frick, Veena Afzal, Axel Visel, Len A. Pennacchio, Diane E. Dickel, Jason P. LerchJacqueline Crawley, Konstantinos Zarbalis, Jill L Silverman, Alexander Nord

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1062-1073
Number of pages12
JournalNature Neuroscience
Volume20
Issue number8
DOIs
StatePublished - Aug 1 2017

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Haploinsufficiency
Brain
Chromatin Assembly and Disassembly
Neuroimmunomodulation
cdc Genes
Frameshift Mutation
Gene Regulatory Networks
Neurogenesis
Interpersonal Relations
Autistic Disorder
RNA
Pathology
Phenotype
Gene Expression
Mutation
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Gompers, A. L., Su-Feher, L., Ellegood, J., Copping, N. A., Riyadh, M. A., Stradleigh, T. W., ... Nord, A. (2017). Germline Chd8 haploinsufficiency alters brain development in mouse. Nature Neuroscience, 20(8), 1062-1073. https://doi.org/10.1038/nn.4592

Germline Chd8 haploinsufficiency alters brain development in mouse. / 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; Zarbalis, Konstantinos; Silverman, Jill L; Nord, Alexander.

In: Nature Neuroscience, Vol. 20, No. 8, 01.08.2017, p. 1062-1073.

Research output: Contribution to journalArticle

Gompers, AL, Su-Feher, L, Ellegood, J, Copping, NA, Riyadh, MA, Stradleigh, TW, Pride, MC, Schaffler, MD, Wade, AA, Catta-Preta, R, Zdilar, I, Louis, S, Kaushik, G, Mannion, BJ, Plajzer-Frick, I, Afzal, V, Visel, A, Pennacchio, LA, Dickel, DE, Lerch, JP, Crawley, J, Zarbalis, K, Silverman, JL & Nord, A 2017, 'Germline Chd8 haploinsufficiency alters brain development in mouse', Nature Neuroscience, vol. 20, no. 8, pp. 1062-1073. https://doi.org/10.1038/nn.4592
Gompers AL, Su-Feher L, Ellegood J, Copping NA, Riyadh MA, Stradleigh TW et al. Germline Chd8 haploinsufficiency alters brain development in mouse. Nature Neuroscience. 2017 Aug 1;20(8):1062-1073. https://doi.org/10.1038/nn.4592
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 ; Zarbalis, Konstantinos ; Silverman, Jill L ; Nord, Alexander. / Germline Chd8 haploinsufficiency alters brain development in mouse. In: Nature Neuroscience. 2017 ; Vol. 20, No. 8. pp. 1062-1073.
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