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CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum

Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains...

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Autores principales: Reddy, Naveen C., Majidi, Shahriyar P., Kong, Lingchun, Nemera, Mati, Ferguson, Cole J., Moore, Michael, Goncalves, Tassia M., Liu, Hai-Kun, Fitzpatrick, James A. J., Zhao, Guoyan, Yamada, Tomoko, Bonni, Azad, Gabel, Harrison W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481233/
https://www.ncbi.nlm.nih.gov/pubmed/34588434
http://dx.doi.org/10.1038/s41467-021-25846-3
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author Reddy, Naveen C.
Majidi, Shahriyar P.
Kong, Lingchun
Nemera, Mati
Ferguson, Cole J.
Moore, Michael
Goncalves, Tassia M.
Liu, Hai-Kun
Fitzpatrick, James A. J.
Zhao, Guoyan
Yamada, Tomoko
Bonni, Azad
Gabel, Harrison W.
author_facet Reddy, Naveen C.
Majidi, Shahriyar P.
Kong, Lingchun
Nemera, Mati
Ferguson, Cole J.
Moore, Michael
Goncalves, Tassia M.
Liu, Hai-Kun
Fitzpatrick, James A. J.
Zhao, Guoyan
Yamada, Tomoko
Bonni, Azad
Gabel, Harrison W.
author_sort Reddy, Naveen C.
collection PubMed
description Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome.
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spelling pubmed-84812332021-10-22 CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum Reddy, Naveen C. Majidi, Shahriyar P. Kong, Lingchun Nemera, Mati Ferguson, Cole J. Moore, Michael Goncalves, Tassia M. Liu, Hai-Kun Fitzpatrick, James A. J. Zhao, Guoyan Yamada, Tomoko Bonni, Azad Gabel, Harrison W. Nat Commun Article Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome. Nature Publishing Group UK 2021-09-29 /pmc/articles/PMC8481233/ /pubmed/34588434 http://dx.doi.org/10.1038/s41467-021-25846-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Reddy, Naveen C.
Majidi, Shahriyar P.
Kong, Lingchun
Nemera, Mati
Ferguson, Cole J.
Moore, Michael
Goncalves, Tassia M.
Liu, Hai-Kun
Fitzpatrick, James A. J.
Zhao, Guoyan
Yamada, Tomoko
Bonni, Azad
Gabel, Harrison W.
CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title_full CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title_fullStr CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title_full_unstemmed CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title_short CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
title_sort charge syndrome protein chd7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481233/
https://www.ncbi.nlm.nih.gov/pubmed/34588434
http://dx.doi.org/10.1038/s41467-021-25846-3
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