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

Research output: Contribution to journalArticle

Corentine Marie, Adrien Clavairoly, Magali Frah, Hatem Hmidan, Jun Yan, Chuntao Zhao, Juliette Van Steenwinckel, Romain Daveau, Bernard Zalc, Bassem Hassan, Jean-Léon Thomas, Pierre Gressens, Philippe Ravassard, Ivan Moszer, Donna M. Martin, Q. Richard Lu, Carlos Parras

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number35
Early online date14 Aug 2018
DOIs
Accepted/In press17 Jul 2018
E-pub ahead of print14 Aug 2018

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Abstract

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective (re)myelination. Mutations in chromatin remodelers CHD7 and CHD8 are the cause of CHARGE syndrome and some autism spectrum disorders (ASD). Here we show that Chd7 protects OPCs from apoptosis by chromatin closing and gene repression of p53, while Chd7 induces chromatin opening and gene activation of OPC-differentiation regulators. Chd7 is, however, dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles, including ASD-risktextendashassociated genes. Our results thus involve oligodendroglia in ASD and CHARGE and offer new avenues to understand and modulate CHD7/CHD8 functions in normal and pathological brain development.Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risktextendashassociated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53. Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17. However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

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