CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation

Author:

Sood SabinaORCID,Weber Christopher M.ORCID,Hodges H. Courtney,Krokhotin Andrey,Shalizi Aryaman,Crabtree Gerald R.

Abstract

The chromatin remodelerCHD8is among the most frequently mutated genes in autism spectrum disorder (ASD). CHD8 has a dosage-sensitive role in ASD, but when and how it becomes critical to human social function is unclear. Here, we conducted genomic analyses of heterozygous and homozygousChd8mouse embryonic stem cells and differentiated neural progenitors. We identify dosage-sensitive CHD8 transcriptional targets, sites of regulated accessibility, and an unexpected cooperation with SOX transcription factors. Collectively, our findings reveal that CHD8 negatively regulates expression of neuronal genes to maintain pluripotency and also during differentiation. Thus, CHD8 is essential for both the maintenance of pluripotency and neural differentiation, providing mechanistic insight into its function with potential implications for ASD.

Funder

Howard Hughes Medical Institute

Simons Foundation

HHS | National Institutes of Health

National Science Foundation

National Institute of Mental Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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