STAG2 promotes the myelination transcriptional program in oligodendrocytes.
STAG2 promotes the myelination transcriptional program in oligodendrocytes.
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DOI：
10.7554/elife.77848
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发表时间：
2022-08-12
期刊：
影响因子：
7.7
通讯作者：
Yu, Hongtao
中科院分区：
文献类型：
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作者：
Cheng, Ningyan;Li, Guanchen;Kanchwala, Mohammed;Evers, Bret M.;Xing, Chao;Yu, Hongtao
内聚蛋白通过DNA环挤压折叠染色体。在其他机制中，内聚蛋白介导的染色体环通过形成远程增强子-启动子相互作用来调节转录。黏结蛋白亚基和调节因子的突变引起称为黏结病的人类发育疾病。脊椎动物黏结蛋白由SMC1、SMC3、RAD21和STAG1或STAG2组成。为了探讨黏结素的生理功能，我们建立了神经系统中Stag2基因缺失的条件敲除（cKO）小鼠。Stag2 cKO小鼠表现出生长迟缓、神经缺陷和过早死亡，部分原因是神经纤维髓鞘形成不足。Stag2 cKO少突胶质细胞表现为成熟延迟和髓鞘相关基因下调。Stag2缺失减少了少突胶质细胞中下调基因的启动子锚定环。因此，stag2 -内聚蛋白在髓形成促进基因上产生启动子锚定环，以促进其转录。我们的研究暗示髓鞘形成缺陷是一个促成黏结病的因素，并建立少突胶质细胞作为相关的细胞类型来探索黏结蛋白调节转录的机制。
Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer–promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelination-related genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelination-promoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.