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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Version of Record online: 27 NOV 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 12, pages 2645–2656, December 2012
How to Cite
Tang, Y., Luo, Y., Jiang, Z., Ma, Y., Lin, C.-J., Kim, C., Carter, M. G., Amano, T., Park, J., Kish, S. and Tian, X. (2012), Jak/Stat3 Signaling Promotes Somatic Cell Reprogramming by Epigenetic Regulation. STEM CELLS, 30: 2645–2656. doi: 10.1002/stem.1225
Author contributions: Y.T.: conception and design, provision of study material, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; Y.L., Z.J., Y.M., and C-J.L.: provision of study material and collection and analysis of data; C.K., M.C., T.A., J.P., M.A., and S.K.: provision of study material; X.C.T.: conception and design, data analysis and interpretation, financial and administrative support, and manuscript writing.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS September 11, 2012.
- Issue online: 27 NOV 2012
- Version of Record online: 27 NOV 2012
- Accepted manuscript online: 11 SEP 2012 10:32AM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 9 MAY 2012
- USDA. Grant Number: 1265-31000-091-02S
- Cell signaling;
- Embryonic stem cells;
- Induced pluripotent stem cells;
Although leukemia inhibitory factor (LIF) maintains the ground state pluripotency of mouse embryonic stem cells and induced pluripotent stem cells (iPSCs) by activating the Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3) pathway, the mechanism remained unclear. Stat3 has only been shown to promote complete reprogramming of epiblast and neural stem cells and partially reprogrammed cells (pre-iPSCs). We investigated if and how Jak/Stat3 activation promotes reprogramming of terminally differentiated mouse embryonic fibroblasts (MEFs). We demonstrated that activated Stat3 not only promotes but also is essential for the pluripotency establishment of MEFs during reprogramming. We further demonstrated that during this process, inhibiting Jak/Stat3 activity blocks demethylation of Oct4 and Nanog regulatory elements in induced cells, which are marked by suppressed endogenous pluripotent gene expression. These are correlated with the significant upregulation of DNA methyltransferase (Dnmt) 1 and histone deacetylases (HDACs) expression as well as the increased expression of lysine-specific histone demethylase 2 and methyl CpG binding protein 2. Inhibiting Jak/Stat3 also blocks the expression of Dnmt3L, which is correlated with the failure of retroviral transgene silencing. Furthermore, Dnmt or HDAC inhibitor but not overexpression of Nanog significantly rescues the reprogramming arrested by Jak/Stat3 inhibition or LIF deprivation. Finally, we demonstrated that LIF/Stat3 signal also represents the prerequisite for complete reprogramming of pre-iPSCs. We conclude that Jak/Stat3 activity plays a fundamental role to promote pluripotency establishment at the epigenetic level, by facilitating DNA demethylation/de novo methylation, and open-chromatin formation during late-stage reprogramming. STEM CELLS 2012;30:2645–2656