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

Autor: Reddy NC; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Majidi SP; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA.; MD-PhD Program, Washington University School of Medicine, St. Louis, MO, 63110, USA., Kong L; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Nemera M; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Ferguson CJ; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Moore M; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Goncalves TM; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Liu HK; Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, German Cancer Research Center Im Neunheimer Feld 280, 69120, Heidelberg, Germany., Fitzpatrick JAJ; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63130, USA.; Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, 63110, USA., Zhao G; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA., Yamada T; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of Neurobiology, Northwestern University, Evanston, IL, 60201, USA., Bonni A; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA. bonni@wustl.edu., Gabel HW; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, 63110, USA. gabelh@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 29; Vol. 12 (1), pp. 5702. Date of Electronic Publication: 2021 Sep 29.
DOI: 10.1038/s41467-021-25846-3
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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