CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum.
CHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum.
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DOI：
10.1038/s41467-021-25846-3
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发表时间：
2021-09-29
影响因子：
16.6
通讯作者：
Gabel HW
中科院分区：
文献类型：
--
作者：
Reddy NC;Majidi SP;Kong L;Nemera M;Ferguson CJ;Moore M;Goncalves TM;Liu HK;Fitzpatrick JAJ;Zhao G;Yamada T;Bonni A;Gabel HW
染色质的调控在大脑发育中起着至关重要的作用。染色质重塑酶CHD7的单倍体不足会导致CHARGE综合征，这是一种影响小脑发育的遗传性疾病。然而，CHD7如何控制小脑中的染色质状态仍未完全清楚。通过在小鼠小脑中的颗粒细胞前体中对CHD7进行条件性敲除，我们发现CHD7强烈促进染色质的可及性、活性组蛋白修饰以及RNA聚合酶在增强子处的募集。体内基因组结构分析显示，CHD7协同调节与增强子激活和拓扑相互作用基因的基因表达相关的表观基因组修饰。基因组和基因本体研究表明，CHD7调节的增强子与控制脑组织形态发生的基因相关。因此，CHD7的条件性敲除引发了小脑多小脑回畸形的显著表型，我们在一个CHARGE综合征病例中也发现了这种情况。最后，我们揭示了在发育中的小脑中颗粒细胞前体分裂的优先方向存在依赖于CHD7的转换，这为CHD7缺失时的小脑多小脑回畸形表型提供了潜在的细胞基础。总之，我们的研究结果明确了CHD7在颗粒细胞前体中的表观基因组调控作用，并确定了CHD7缺失时小脑模式的异常，这对我们理解CHARGE综合征具有潜在意义。
影响小脑发育的CHARGE综合征可由染色质重塑酶CHD7的单倍体不足引起；然而，CHD7的确切作用仍不清楚。在这里，作者表明CHD7促进颗粒细胞前体中的染色质可及性和增强子活性，并调节小脑皮质的形态发生，其中CHD7的缺失会引发小脑多小脑回畸形。
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.
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影响因子：
15.9
作者：
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通讯作者：
West AE
DOI：
10.1097/nen.0000000000000171
发表时间：
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