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

Developmental cell | 2018

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.

Pubmed ID: 29920279 RIS Download

Mesh terms: Animals | Cell Differentiation | Chromatin | Chromatin Assembly and Disassembly | DNA Helicases | DNA-Binding Proteins | Histone Methyltransferases | Histone-Lysine N-Methyltransferase | Mice | Mice, Knockout | Myelin Sheath | Nerve Fibers, Myelinated | Nuclear Proteins | Oligodendroglia | Rats | Rats, Sprague-Dawley | Transcription Factors

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Antibodies used in this publication

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Anti-O4, clone 81 (also referred to in the literature as mAB O4) antibody (antibody)


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CHD8 antibody (antibody)


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Cleaved Caspase-3 (Asp175) Antibody (antibody)


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Trimethyl-Histone H3 (Lys4) antibody (antibody)


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GFAP Monoclonal Antibody (2.2B10) (antibody)


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Software tool for manipulating alignments in SAM format for storing nucleotide sequence alignment, including sorting, merging, indexing and generating alignments in per position format. Parts that are relevant to genetic analysis include SNP and indel callings.

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