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Jak/Stat3 Signaling Promotes Somatic Cell Reprogramming by Epigenetic Regulation

Cited 65 time in Web of Science Cited 73 time in Scopus
Authors

Tang, Yong; Luo, Yan; Jiang, Zongliang; Ma, Yinghong; Lin, Chih-Jen; Kim, Chul; Carter, Mark G.; Amano, Tomokazu; Park, Joonghong; Kish, Sharon; Tian, Xiuchun (Cindy)

Issue Date
2012-12
Publisher
AlphaMed Press Inc
Citation
Stem Cells, Vol.30 No.12, pp.2645-2656
Abstract
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
ISSN
1066-5099
URI
https://hdl.handle.net/10371/203898
DOI
https://doi.org/10.1002/stem.1225
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