Zfp281 Coordinates Opposing Functions of Tet1 and Tet2 in Pluripotent States.
Zfp281 Coordinates Opposing Functions of Tet1 and Tet2 in Pluripotent States.
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DOI：
10.1016/j.stem.2016.05.025
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发表时间：
2016-09-01
期刊：
影响因子：
23.9
通讯作者：
Wang, Jianlong
中科院分区：
文献类型：
--
作者：
Fidalgo, Miguel;Huang, Xin;Guallar, Diana;Sanchez-Priego, Carlos;Valdes, Victor Julian;Saunders, Arven;Ding, Junjun;Wu, Wen-Shu;Clavel, Carlos;Wang, Jianlong
多能性越来越多地被认为是一系列细胞状态，由其生长条件定义。虽然幼稚和引发的多能性状态已被分子表征，但我们对调节状态获得的事件的理解是不够的。在这里，我们进行了小鼠胚胎干细胞（ESC）的比较RNA测序，并定义了一个多能细胞命运（PCF）基因签名与收购幼稚和启动多能性。我们确定Zfp 281作为启动多能性的关键转录调节因子，其也作为在小鼠和人ESC中实现幼稚多能性的障碍。从机制上讲，Zfp 281与Tet 1相互作用，但不与Tet 2相互作用，其直接转录靶标miR-302/367负调控Tet 2表达，以建立和维持引发的多能性。相反，异位Tet 2单独，而不是Tet 1，有效地重编程致敏细胞向幼稚多能性。我们的研究揭示了一个分子回路，其中Tet 1和Tet 2的相反功能控制替代多能状态的获取。
Pluripotency is increasingly recognized as a spectrum of cell states, defined by their growth conditions. Although naïve and primed pluripotency states have been characterized molecularly, our understanding about events regulating state acquisition is wanting. Here, we performed comparative RNA sequencing of mouse embryonic stem cells (ESCs) and defined a pluripotent cell fate (PCF) gene signature associated with acquisition of naive and primed pluripotency. We identify Zfp281 as a key transcriptional regulator for primed pluripotency that also functions as a barrier towards achieving naive pluripotency in both mouse and human ESCs. Mechanistically, Zfp281 interacts with Tet1, but not Tet2, and its direct transcriptional target miR-302/367 negatively regulate Tet2 expression to establish and maintain primed pluripotency. Conversely, ectopic Tet2 alone, but not Tet1, efficiently reprograms primed cells towards naive pluripotency. Our study reveals a molecular circuitry in which opposing functions of Tet1 and Tet2 control acquisition of alternative pluripotent states.
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