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

Naveen C. Reddy, Shahriyar P. Majidi, Lingchun Kong, Mati Nemera, Cole J. Ferguson, Michael Moore, Tassia M. Goncalves, Hai-Kun Liu, James A. J. Fitzpatrick, Guoyan Zhao, Tomoko Yamada, Azad Bonni () and Harrison W. Gabel ()
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Naveen C. Reddy: Washington University School of Medicine
Shahriyar P. Majidi: Washington University School of Medicine
Lingchun Kong: Washington University School of Medicine
Mati Nemera: Washington University School of Medicine
Cole J. Ferguson: Washington University School of Medicine
Michael Moore: Washington University School of Medicine
Tassia M. Goncalves: Washington University School of Medicine
Hai-Kun Liu: Division of Molecular Neurogenetics, DKFZ-ZMBH Alliance, German Cancer Research Center Im Neunheimer Feld 280
James A. J. Fitzpatrick: Washington University School of Medicine
Guoyan Zhao: Washington University School of Medicine
Tomoko Yamada: Washington University School of Medicine
Azad Bonni: Washington University School of Medicine
Harrison W. Gabel: Washington University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25846-3

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