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

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.

Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8

“…This partial requirement of Chd7 during differentiation/maturation of Chd7 -deficient OPCs result at least in part from a functional compensation provided by Chd8 which, like Chd7, binds to the majority of OL differentiation genes in OPCs. Together with our previous report on Chd7 expression during OL differentiation and myelination ( 28 ), and our complementary study on Chd8 LOF in OL lineage cells ( 37 ), the present results underscore CHD chromatin remodelers as key regulators of the progression along the differentiation/maturation pathway in OL lineage cells.…”

“…Given that we integrated ChIP-seq datasets obtained from rat and mouse, we asked whether binding is conserved between species. To address this question, we compared the Chd8-binding profile between our in vivo mouse-purified O4 + cells with rat OPC primary cultures ( 37 ) and observed a large overlap (87%) ( SI Appendix , Fig. S5 B ) of bound genes between species, comparable to the reported overlap of Chd8 ChIP-seq replicates from the same sample ( 36 , 38 ).…”

In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with Autism risk genes

“…One of the risk genes, Chd8, encodes a protein that binds directly to b-catenin and negatively regulates the Wnt signaling pathway, which plays a crucial role in progenitor proliferation and differentiation in the forebrain (Sakamoto et al, 2000;Durak et al, 2016;Katayama et al, 2016;Platt et al, 2017). Our results showed that Chd8 modulates gene programs for oligodendrocyte differentiation and maturation, consistent with previously reported ChIP-Seq results showing that CHD8 interacts directly with OPC maturation genes in the neonatal stage Zhao et al, 2018). Other cell types may be altered at different developmental stages, through cell-autonomous (intrinsic) or non-cell autonomous (extrinsic) mechanisms, which should be investigated further in the future.…”

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination

“…The variability in behavioral phenotypes between the different Chd8 mutant lines also calls into question the generalizability of the cellular and molecular phenotypes reported in other studies. However, important discoveries have been made that indicate a possible mechanism linking Chd8 deficiency to altered behavior, including delayed neurodevelopment [Katayama et al, 2016], myelination defects [Zhao et al, 2018], increased proliferation of neuronal progenitors [Gompers et al, 2017], increased total brain volume and volumetric increases of several brain regions [Suetterlin et al, 2018], and changes in inhibitory synaptic transmission [Jung et al, 2018]. Side-by-side comparisons of the different mutant lines could be informative after a more complete understanding of the transcriptional regulation of CHD8 is obtained.…”