title: 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.
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.
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: W-T
authors.initials: WT
authors.lastname: Guo
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: X-W
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Yan
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Y-P
authors.initials: YP
authors.lastname: Li
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Yin
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Urology, Center of Reproductive Sciences, and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Melton
authors.affiliation: Department of Urology, Center of Reproductive Sciences, and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shenoy
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Reyes
authors.affiliation: Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Oakes
authors.affiliation: Department of Urology, Center of Reproductive Sciences, and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Blelloch
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D000066673:Cell Self Renewal / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C556303:MIRN294 microRNA, mouse; C558265:MIRN302 microRNA, mouse; D035683:MicroRNAs; C542687:mirnlet7 microRNA, mouse