CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
| Autor: | Hai-Kun Liu, Michael P. Moore, Tassia Mangetti Gonçalves, Naveen C. Reddy, James A. J. Fitzpatrick, Azad Bonni, Cole J. Ferguson, Mati Nemera, Harrison W. Gabel, Shahriyar P. Majidi, Lingchun Kong, Tomoko Yamada, Guoyan Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cerebellum
Science General Physics and Astronomy General Biochemistry Genetics and Molecular Biology Chromatin remodeling Article Epigenesis Genetic Mice Neural Stem Cells Conditional gene knockout medicine Morphogenesis Animals Humans RNA-Seq Epigenetics in the nervous system Enhancer Epigenomics Mice Knockout Neurons Multidisciplinary biology DNA Helicases Gene Expression Regulation Developmental Infant Development of the nervous system General Chemistry Granule cell Chromatin Assembly and Disassembly Cell biology Chromatin DNA-Binding Proteins Histone Code Disease Models Animal medicine.anatomical_structure Histone Enhancer Elements Genetic Polymicrogyria Mutation biology.protein Epigenetics Gene expression CHARGE Syndrome Cell Division |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. CHARGE syndrome that affects cerebellar development can be caused by haploinsufficiency of the chromatin remodeling enzyme CHD7; however the precise role of CHD7 remains unknown. Here the authors show CHD7 promotes chromatin accessibility and enhancer activity in granule cell precursors and regulates morphogenesis of the cerebellar cortex, where loss of CHD7 triggers cerebellar polymicrogyria. |
| Databáze: | OpenAIRE |
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