The THO Complex Regulates Pluripotency Gene mRNA Export and Controls Embryonic Stem Cell Self-Renewal and Somatic Cell Reprogramming

• Published in: Cell stem cell Vol. 13; no. 6; pp. 676 - 690
• Main Authors: Wang, Li, Miao, Yi-Liang, Zheng, Xiaofeng, Lackford, Brad, Zhou, Bingying, Han, Leng, Yao, Chengguo, Ward, James M., Burkholder, Adam, Lipchina, Inna, Fargo, David C., Hochedlinger, Konrad, Shi, Yongsheng, Williams, Carmen J., Hu, Guang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2013
• Subjects: Animals; Blastocyst - cytology; Blastocyst - metabolism; Cell Differentiation - genetics; Cell Line; Cell Proliferation; Cellular Reprogramming - genetics; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Mice; Models, Biological; Multiprotein Complexes - metabolism; Pluripotent Stem Cells - metabolism; Protein Binding - genetics; RNA Transport - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 1934-5909; 1875-9777
• 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. [Display omitted] •THO is required for embryonic stem cell (ESC) self-renewal•THO binds to pluripotency gene transcripts and controls their export through Thoc5•Thoc5 level is a key determinant of ESC differentiation kinetics•THO is required for somatic cell reprogramming and mouse blastocyst development Preferential interaction of pluripotency network component mRNAs with the THO complex mediates their export from the nucleus and is important for establishment and maintenance of the pluripotent state.