Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Cell Stem Cell. 2013 Dec 5;13(6):676-90. doi: 10.1016/j.stem.2013.10.008.
Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, posttranscriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5 and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, because its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of posttranscriptional regulation in stem cell fate specification.
胚胎干细胞 (ESC) 的自我更新和分化受广泛的调控网络控制。尽管已经广泛研究了涉及的转录调控机制，但对转录后调控仍知之甚少。在这里，我们描述了 THO 复合物在 ESC 自我更新和分化中的关键作用。我们表明，THO 通过 Thoc5 优先与多能性基因转录本相互作用，并通过调节它们的输出和表达来至少部分地维持自我更新。在分化过程中，由于 Thoc5 表达减少，THO 与其转录本的相互作用丧失，导致多能性蛋白表达减少，从而有利于退出自我更新。THO 对于建立多能性也很重要，因为其耗竭会抑制体细胞重编程和囊胚发育。总之，我们的数据表明，THO 调节多能性基因 mRNA 的输出以控制 ESC 的自我更新和分化，因此揭示了转录后调控在干细胞命运特化中的作用。
