期刊
CELL RESEARCH
卷 23, 期 1, 页码 142-156出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2012.180
关键词
Sox2; miR-29b; Dnmt; reprogramming; MET; Dlk1-Dio3
类别
资金
- Ministry of Science and Technology [2011CB965100, 2011DFA30480, 2010CB944900, 2010CB945000, 2011CBA01100]
- National Natural Science Foundation of China [91219305, 31071306, 31101061, 31210103905, 90919028, 31000378, 31171432, 30971451]
- Science and Technology Commission of Shanghai Municipality [11ZR1438500, 11XD1405300]
- Ministry of Education [IRT1168, 20110072110039]
- Chen Guang project
- Shanghai Municipal Education Commission
- Shanghai Education Development Foundation [12CG19]
- Fundamental Research Funds for the Central Universities
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 Dlk1-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 signaling axis that regulates DNA methylation-related events during reprogramming.
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