microRNA-29b is a novel mediator of Sox2 function in the regulation of somatic cell reprogramming  

作　　者：Xudong Guo Qidong Liu Guiying Wang Songcheng Zhu Longfei Gao Wujun Hong Yafang Chen Minjuan Wu Houqi Liu Cizhong Jiang Jiuhong Kang 

机构地区：[1]Clinical and Translational Research Center of Shanghai First Maternity & Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China [2]Department of Embryology and Histology, Second Military Medical University, Shanghai 200433, China

出　　处：《Cell Research》2013年第1期142-156,共15页细胞研究（英文版）

基　　金：This work was supported by grants from the Ministry of Science and Technology （2011CB965100, 2011DFA30480, 2010CB944900, 2010CB945000, and 2011CBA01100）, the National Natural Science Foundation of China （91219305, 31071306, 31101061, 31210103905, 90919028, 31000378, 31171432, and 30971451）, the Science and Technology Commission of Shanghai Municipality （11ZR1438500 and 11XD1405300）, and the Ministry of Education （IRT1168 and 20110072110039）. The work was also supported by the ＂Chen Guang＂ project, the Shanghai Municipal Education Commission and Shanghai Education Development Foundation （12CG19） and the Fundamental Research Funds for the Central Universities.

摘　　要：Fibroblasts can be reprogrammed into induced pluripotent stem cells （iPSCs） by the application of Yamanaka factors （OSKM）, but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b （miR-29b） expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition （MET） and Dlkl-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT sig- naling axis that regulates DNA methylation-related events during reprogramming.Fibroblasts can be reprogrammed into induced pluripotent stem cells （iPSCs） by the application of Yamanaka factors （OSKM）, but the mechanisms underlying this reprogramming remain poorly understood. Here, we report that Sox2 directly regulates endogenous microRNA-29b （miR-29b） expression during iPSC generation and that miR-29b expression is required for OSKM- and OSK-mediated reprogramming. Mechanistic studies show that Dnmt3a and Dnmt3b are in vivo targets of miR-29b and that Dnmt3a and Dnmt3b expression is inversely correlated with miR-29b expression during reprogramming. Moreover, the effect of miR-29b on reprogramming can be blocked by Dnmt3a or Dnmt3b overexpression. Further experiments indicate that miR-29b-DNMT signaling is significantly involved in the regulation of DNA methylation-related reprogramming events, such as mesenchymal-to-epithelial transition （MET） and Dlkl-Dio3 region transcription. Thus, our studies not only reveal that miR-29b is a novel mediator of reprogramming factor Sox2 but also provide evidence for a multistep mechanism in which Sox2 drives a miR-29b-DNMT sig- naling axis that regulates DNA methylation-related events during reprogramming.

关 键 词：SOX2 miR-29b DNMT rcprogramming MET Dlkl-Dio3 

分 类 号：Q132.7[生物学—普通生物学] Q785