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

• Published in: Developmental cell Vol. 45; no. 6; pp. 753 - 768.e8
• Main Authors: Zhao, Chuntao, Dong, Chen, Frah, Magali, Deng, Yaqi, Marie, Corentine, Zhang, Feng, Xu, Lingli, Ma, Zhixing, Dong, Xinran, Lin, Yifeng, Koenig, Scott, Nait-Oumesmar, Brahim, Martin, Donna M., Wu, Laiman N., Xin, Mei, Zhou, Wenhao, Parras, Carlos, Lu, Q. Richard
• Format: Journal Article
• Language: English
• Published: 18.06.2018
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2018.05.022

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 re-myelination. 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. Mutations in chromatin regulator CHD8 are associated with autism and white matter abnormalities. Zhao et al. show that CHD8 functions in oligodendrocyte progenitors to promote oligodendrocyte lineage development, myelination, and post-injury re-myelination by establishing an open chromatin landscape for a cascade of chromatin reprogramming events and recruiting KMT2 histone methyltransferase.