Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair

Dev Cell. 2018 Jun 18;45(6):753-768.e8. doi: 10.1016/j.devcel.2018.05.022.

Abstract

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.

Keywords: CHD8; KMT2/MLL; autism; chromatin landscape; chromatin remodeling; histone methyltransferase; myelin repair; myelination; oligodendrocyte development; regulatory cascade.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly / physiology*
  • DNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Mice
  • Mice, Knockout
  • Myelin Sheath / metabolism
  • Myelin Sheath / physiology
  • Nerve Fibers, Myelinated / metabolism*
  • Nuclear Proteins / metabolism*
  • Oligodendroglia / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / metabolism

Substances

  • Chd8 protein, rat
  • Chromatin
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • DNA Helicases