Developmental Cell
Volume 45, Issue 6, 18 June 2018, Pages 753-768.e8
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Article
Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair

https://doi.org/10.1016/j.devcel.2018.05.022Get rights and content
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Highlights

  • Autism-associated CHD8 required for oligodendrocyte development and survival

  • Chromatin regulator CHD8 required for OPC proliferation and remyelination

  • CHD8-BRG1-CHD7 cascade regulates oligodendroglial lineage progression

  • CHD8 recruits KMT2 histone methyltransferase to promote oligodendrocyte development

Summary

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
chromatin remodeling
autism
myelination
chromatin landscape
regulatory cascade
KMT2/MLL
histone methyltransferase
oligodendrocyte development
myelin repair

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