title: Jak/Stat3 signaling promotes somatic cell reprogramming by epigenetic regulation.
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.
authors.affiliation: Center for Regenerative Biology, Department of Animal Science, University of Connecticut, Storrs, Connecticut 06269, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Zongliang
authors.initials: Z
authors.lastname: Jiang
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Ma
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Lin
authors.forename: Chul
authors.initials: C
authors.lastname: Kim
authors.forename: Mark G
authors.initials: MG
authors.lastname: Carter
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Amano
authors.forename: Joonghong
authors.initials: J
authors.lastname: Park
authors.forename: Sharon
authors.initials: S
authors.lastname: Kish
authors.forename: Xiuchun Cindy
authors.initials: XC
authors.lastname: Tian
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D057890:Epigenomics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053612:Janus Kinases