| MicroRNA-302 Increases Reprogramming Efficiency via Repression of NR2F2. | |
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MedLine Citation:
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PMID: 23136034 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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MicroRNAs (miRNAs) have emerged as critical regulators of gene expression through translational inhibition and RNA decay, and have been implicated in the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. In this study, we use global bioinformatics analysis of miRNA and mRNA microarrays to predict novel miRNA-mRNA interactions in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). In particular, we demonstrate a regulatory feedback loop between the miR-302 cluster and two transcription factors, NR2F2 and OCT4. Our data show high expression of miR-302 and OCT4 in pluripotent cells, while NR2F2 is expressed exclusively in differentiated cells. Target analysis predicts that NR2F2 is a direct target of the miR-302, which we experimentally confirm by reporter luciferase assays and real-time PCR. We also demonstrate that NR2F2 directly inhibits the activity of the OCT4 promoter and thus diminishes the positive feedback loop between OCT4 and the miR-302. Importantly, higher reprogramming efficiencies were obtained when we reprogrammed human adipose-derived stem cells (hASCs) into iPSCs using four factors (KLF4, C-MYC, OCT4, and SOX2) plus miR-302 (this reprogramming cocktail is hereafter referred to as "KMOS3") when compared to using four factors ("KMOS"). Furthermore, shRNA knockdown of NR2F2 mimics the over-expression of miR-302 by also enhancing reprogramming efficiency. Interestingly, we were unable to generate iPSCs from miR-302a/b/c/d alone, which is in contrast to previous publications that have reported that miR-302 by itself can reprogram human skin cancer cells and human hair follicle cells. Taken together, these findings demonstrate that miR-302 inhibits NR2F2 and promotes pluripotency through indirect positive regulation of OCT4. This feedback loop represents an important new mechanism for understanding and inducing pluripotency in somatic cells. |
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Authors:
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Shijun Hu; Kitchener D Wilson; Zhumur Ghosh; Leng Han; Yongming Wang; Feng Lan; Katherine J Ransohoff; Joseph C Wu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-8 |
Journal Detail:
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Title: Stem cells (Dayton, Ohio) Volume: - ISSN: 1549-4918 ISO Abbreviation: Stem Cells Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9304532 Medline TA: Stem Cells Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 AlphaMed Press. |
Affiliation:
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Department of Medicine, Division of Cardiology, Stanford University; Cardiovascular Institute, Stanford University; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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