1. Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells.
- Author
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Guo WT, Wang XW, Yan YL, Li YP, Yin X, Zhang Q, Melton C, Shenoy A, Reyes NA, Oakes SA, Blelloch R, and Wang Y
- Subjects
- Animals, Apoptosis, Embryonic Stem Cells metabolism, Mice, Signal Transduction, Cell Self Renewal physiology, Embryonic Stem Cells physiology, Epithelial-Mesenchymal Transition physiology, MicroRNAs physiology
- Abstract
The embryonic stem cell (ESC)-enriched miR-294/302 family and the somatic cell-enriched let-7 family stabilizes the self-renewing and differentiated cell fates, respectively. The mechanisms underlying these processes remain unknown. Here we show that among many pathways regulated by miR-294/302, the combinatorial suppression of epithelial-mesenchymal transition (EMT) and apoptotic pathways is sufficient in maintaining the self-renewal of ESCs. The silencing of ESC self-renewal by let-7 was accompanied by the upregulation of several EMT regulators and the induction of apoptosis. The ectopic activation of either EMT or apoptotic program is sufficient in silencing ESC self-renewal. However, only combined but not separate suppression of the two programs inhibited the silencing of ESC self-renewal by let-7 and several other differentiation-inducing miRNAs. These findings demonstrate that combined repression of the EMT and apoptotic pathways by miR-294/302 imposes a synergistic barrier to the silencing of ESC self-renewal, supporting a model whereby miRNAs regulate complicated cellular processes through synergistic repression of multiple targets or pathways.
- Published
- 2015
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