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

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

doi:10.1073/pnas.1802620115

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

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

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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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	35
Early online date	14 Aug 2018
DOIs	https://doi.org/10.1073/pnas.1802620115
Publication status	E-pub ahead of print - 14 Aug 2018

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http://www.pnas.org/content/early/2018/08/13/1802620115

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Marie, C., Clavairoly, A., Frah, M., Hmidan, H., Yan, J., Zhao, C., Van Steenwinckel, J., Daveau, R., Zalc, B., Hassan, B., Thomas, J.-L., Gressens, P., Ravassard, P., Moszer, I., Martin, D. M., Lu, Q. R., & Parras, C. (2018). Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8. Proceedings of the National Academy of Sciences of the United States of America, 115(35). Advance online publication. https://doi.org/10.1073/pnas.1802620115

@article{a417d39526934ca6a665157d122f10f7,

title = "Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8",

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.",

author = "Corentine Marie and Adrien Clavairoly and Magali Frah and Hatem Hmidan and Jun Yan and Chuntao Zhao and {Van Steenwinckel}, Juliette and Romain Daveau and Bernard Zalc and Bassem Hassan and Jean-L{\'e}on Thomas and Pierre Gressens and Philippe Ravassard and Ivan Moszer and Martin, {Donna M.} and Lu, {Q. Richard} and Carlos Parras",

year = "2018",

month = aug,

day = "14",

doi = "10.1073/pnas.1802620115",

language = "English",

volume = "115",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "35",

}

Marie, C, Clavairoly, A, Frah, M, Hmidan, H, Yan, J, Zhao, C, Van Steenwinckel, J, Daveau, R, Zalc, B, Hassan, B, Thomas, J-L, Gressens, P, Ravassard, P, Moszer, I, Martin, DM, Lu, QR & Parras, C 2018, 'Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 35. https://doi.org/10.1073/pnas.1802620115

TY - JOUR

T1 - Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8

AU - Marie, Corentine

AU - Clavairoly, Adrien

AU - Frah, Magali

AU - Hmidan, Hatem

AU - Yan, Jun

AU - Zhao, Chuntao

AU - Van Steenwinckel, Juliette

AU - Daveau, Romain

AU - Zalc, Bernard

AU - Hassan, Bassem

AU - Thomas, Jean-Léon

AU - Gressens, Pierre

AU - Ravassard, Philippe

AU - Moszer, Ivan

AU - Martin, Donna M.

AU - Lu, Q. Richard

AU - Parras, Carlos

PY - 2018/8/14

Y1 - 2018/8/14

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1802620115

DO - 10.1073/pnas.1802620115

M3 - Article

SN - 0027-8424

VL - 115

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 35

ER -

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

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