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.
Original language | English (US) |
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Article number | 5702 |
Journal | Nature communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - Dec 1 2021 |
Funding
We thank members of the Bonni laboratory for helpful discussions and critical reading of the manuscript, the Washington University Center for Cellular Imaging (WUCCI) (NIH OD021694), which is supported by Washington University School of Medicine, the Genome Technology Access Center (GTAC) and Center for Genomic Sciences (CGS) at Washington University in St. Louis for sequencing services. Supported by NIH grant NS041021 (A.B. and HWG), the Mathers Foundation (A.B.), the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital grants CDI-CORE-2015-505 and CDI-CORE-2019-813, and NIH OD021694 grant (WUCCI).
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy