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

Naveen C Reddy,Tassia M Goncalves,Tomoko Yamada,Guoyan Zhao,Harrison W Gabel,Cole J Ferguson,Hai-Kun Liu,Shahriyar P Majidi,Mati Nemera,Azad Bonni,James A J Fitzpatrick,Michael Moore,Lingchun Kong

doi:10.1038/s41467-021-25846-3

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.

Highlights

Regulation of chromatin plays fundamental roles in the development of the brain
To elucidate the epigenetic regulatory role of CHD7 during cerebellar development, we first characterized the genomic binding of CHD7 in the mouse cerebellum at postnatal day 4 (P4), a period of peak granule cell precursor expansion
These results indicate that CHD7 occupies diverse accessible genomic regulatory elements in granule cell precursors of the developing cerebellum

Summary

Introduction

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. CHD7 chromatin remodeling function remains to be studied in the context of a multilayered epigenetic regulatory program that integrates genome architecture with chromatin accessibility, transcriptional activity state, and gene expression. We uncover that conditional CHD7 knockout leads to a switch in the preferred axis of granule cell precursor division Consistent with these findings in mice, genes bound by CHD7 in the fetal human cerebellum are implicated in disorders of brain folding. Our findings suggest that CHD7 governs enhancer and transcriptional activation in granule cell precursors during a window of cerebellar development that controls cerebellar cortical morphogenesis, thereby offering potential mechanisms by which epigenetic factors contribute to brain folding during development and disease

Methods

Results

Conclusion