Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation

Wang G.; Guo X.; Hong W.Liu Q.Wei T.Lu C.Gao L.Ye D.Zhou Y.Chen J.Wang J.Wu M.Liu H.Kang J.

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Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation

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Fibroblasts can be reprogrammed to induced pluripotent stem cells (iPSCs) by application of transcription factors octamer-binding protein 4 (Oct4), SRY-box containing gene 2 (Sox2), Kruppel-like factor 4 (Klf4), and c-Myelocytomatosis oncogene (c-Myc) (OSKM), but the underlying mechanisms remain unclear. Here, we report that exogenous Oct4 and Sox2 can bind at the promoter regions of mir-141/200c and mir-200a/b/429 cluster, respectively, and induce the transcription activation of miR-200 family during the OSKM-induced reprogramming. Functional suppression of miR-200s with specific inhibitors significantly represses the OSKM-caused mesenchymalto-epithelial transition (MET, an early event in reprogramming of fibroblasts to iPSCs) and iPSC generation, whereas overexpression of miR-200s promotes the MET and iPSC generation. Mechanistic studies showed that miR-200s significantly repress the expression of zinc finger E-box binding homeobox 2 (ZEB2) through directly targeting its 3' UTR and direct inhibition of ZEB2 can mimic the effects of miR-200s on iPSC generation and MET process. Moreover, the effects of miR-200s during iPSC generation can be blocked by ZEB2 overexpression. Collectively, our findings not only reveal that members of the miR-200 family are unique mediators of the reprogramming factors Oct4/Sox2, but also demonstrate that the miR-200/ZEB2 pathway as one critical mechanism of Oct4/Sox2 to induce somatic cell reprogramming at the early stage.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第8期|2858-2863|共6页
作者
Wang G.; Guo X.; Hong W.Liu Q.Wei T.Lu C.Gao L.Ye D.Zhou Y.Chen J.Wang J.Wu M.Liu H.Kang J.;
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作者单位

Department of Embryology and Histology, Second Military Medical University, Shanghai 200433, China;

Shanghai First Maternity and Infant Health Hospital, School of Life Science and Technology, Tongji University, Shanghai 200092, China;

Laboratory of Population and Quantitative Genetics, School of Life Sciences, Fudan University, Shanghai 200433, ChinaDepartment of Hematology, Changhai Hospital, Shanghai 200433, China;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
MicroRNAs; Pluripotency; SMAD interacting protein 1;

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Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation

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