Topoisomerase IIA in adult NSCs regulates SVZ neurogenesis by transcriptional activation of Usp37.
Topoisomerase IIA in adult NSCs regulates SVZ neurogenesis by transcriptional activation of Usp37.
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成年 NSC 中的拓扑异构酶 IIA 通过 Usp37 的转录激活调节 SVZ 神经发生
DOI：
10.1093/nar/gkac731
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发表时间：
2022-09-09
影响因子：
14.9
通讯作者：
He, Cheng
中科院分区：
文献类型：
--
作者：
Qin, Shangyao;Yuan, Yimin;Huang, Xiao;Tan, Zijian;Hu, Xin;Liu, Hong;Pu, Yingyan;Ding, Yu-qiang;Su, Zhida;He, Cheng
摘要拓扑异构酶Ⅱ A（Topoisomerase Ⅱ A，TOP 2a）是一种重要的解除DNA双链缠结和扭转应力的酶。然而，它在基因组转录调控中的功能在很大程度上仍然未知，特别是在成年神经发生期间。在这里，我们表明，TOP 2a优先表达在成年小鼠大脑中的神经原性壁龛，如脑室下区（SVZ）。条件性敲除SVZ的成体神经干细胞（NSCs）中的Top 2a显著抑制其自我更新和增殖，并最终减少神经发生。为了深入了解TOP 2a调控成体神经干细胞的分子机制，我们进行了RNA测序（RNA-Seq）和染色质免疫沉淀测序（ChIP-Seq），并将泛素特异性蛋白酶37（Usp 37）鉴定为直接的TOP 2a靶基因。重要的是，Usp 37的过表达足以挽救由Top 2a敲低引起的成体NSC的受损的自我更新能力。综上所述，这项原理验证研究阐明了TOP 2a/Usp 37介导的成人神经发生的新分子机制，这将显着扩大我们对拓扑异构酶在成人大脑中功能的理解。
Abstract Topoisomerase IIA (TOP2a) has traditionally been known as an important nuclear enzyme that resolves entanglements and relieves torsional stress of DNA double strands. However, its function in genomic transcriptional regulation remains largely unknown, especially during adult neurogenesis. Here, we show that TOP2a is preferentially expressed in neurogenic niches in the brain of adult mice, such as the subventricular zone (SVZ). Conditional knockout of Top2a in adult neural stem cells (NSCs) of the SVZ significantly inhibits their self-renewal and proliferation, and ultimately reduces neurogenesis. To gain insight into the molecular mechanisms by which TOP2a regulates adult NSCs, we perform RNA-sequencing (RNA-Seq) plus chromatin immunoprecipitation sequencing (ChIP-Seq) and identify ubiquitin-specific protease 37 (Usp37) as a direct TOP2a target gene. Importantly, overexpression of Usp37 is sufficient to rescue the impaired self-renewal ability of adult NSCs caused by Top2a knockdown. Taken together, this proof-of-principle study illustrates a TOP2a/Usp37-mediated novel molecular mechanism in adult neurogenesis, which will significantly expand our understanding of the function of topoisomerase in the adult brain.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
64.5
作者：
Bonaguidi MA;Wheeler MA;Shapiro JS;Stadel RP;Sun GJ;Ming GL;Song H
通讯作者：
Song H
影响因子：
5.2
作者：
Ben-David, Uri;Cowell, Ian G.;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
4.3
作者：
MacIsaac KD;Lo KA;Gordon W;Motola S;Mazor T;Fraenkel E
通讯作者：
Fraenkel E