期刊
DEVELOPMENTAL CELL
卷 45, 期 6, 页码 753-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2018.05.022
关键词
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资金
- US National Institutes of Health [R01NS072427, R01NS075243]
- National Multiple Sclerosis Society [RG1508, NMSS RG-1501-02851]
- CHARGE Syndrome Foundation
- National Natural Science Foundation of China [81720108018]
- Fondation pour l'Aide a la Recherche sur la Sclerose en Plaques (ARSEP)
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 inmyelination 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.
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