CHD8 dosage regulates transcription in pluripotency and early murine neural differentiation

Proc Natl Acad Sci U S A. 2020 Sep 8;117(36):22331-22340. doi: 10.1073/pnas.1921963117. Epub 2020 Aug 24.


The chromatin remodeler CHD8 is 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 homozygous Chd8 mouse 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.

Keywords: autism spectrum disorder (ASD); chromatin remodeling; chromodomain helicase DNA-binding protein 8 (CHD8); neural progenitors; pluripotency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autism Spectrum Disorder
  • Cells, Cultured
  • Chromatin Assembly and Disassembly / genetics
  • DNA-Binding Proteins* / genetics
  • DNA-Binding Proteins* / metabolism
  • Embryonic Stem Cells / metabolism
  • Gene Dosage / genetics*
  • Mice
  • Mice, Knockout
  • Neurogenesis / genetics*


  • DNA-Binding Proteins
  • duplin protein, mouse