title: Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation.
abstract: 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 mesenchymal-to-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.
authors: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology,  Tongji University, Shanghai 200092,  People's Republic of China.
authors: Guiying
authors: G
authors: Wang
authors: Xudong
authors: X
authors: Guo
authors: Wujun
authors: W
authors: Hong
authors: Qidong
authors: Q
authors: Liu
authors: Tingyi
authors: T
authors: Wei
authors: Chenqi
authors: C
authors: Lu
authors: Longfei
authors: L
authors: Gao
authors: Dan
authors: D
authors: Ye
authors: Yi
authors: Y
authors: Zhou
authors: Jie
authors: J
authors: Chen
authors: Jianmin
authors: J
authors: Wang
authors: Minjuan
authors: M
authors: Wu
authors: Houqi
authors: H
authors: Liu
authors: Jiuhong
authors: J
authors: Kang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D018398:Homeodomain Proteins / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D018398:Homeodomain Proteins; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012097:Repressor Proteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2
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