miR-294/miR-302 Promotes Proliferation, Suppresses G1-S Restriction Point, and Inhibits ESC Differentiation through Separable Mechanisms
Yangming Wang,
Collin Melton,
Ya-Pu Li,
Archana Shenoy,
Xin-Xin Zhang,
Deepa Subramanyam,
Robert Blelloch
Affiliations
Yangming Wang
Peking-Tsinghua Joint Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing 100871, China
Collin Melton
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, San Francisco, CA 94143, USA
Ya-Pu Li
Peking-Tsinghua Joint Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing 100871, China
Archana Shenoy
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, San Francisco, CA 94143, USA
Xin-Xin Zhang
Peking-Tsinghua Joint Center for Life Sciences, Institute of Molecular Medicine, Peking University, Beijing 100871, China
Deepa Subramanyam
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, San Francisco, CA 94143, USA
Robert Blelloch
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, San Francisco, CA 94143, USA
The miR-294 and miR-302 microRNAs promote the abbreviated G1 phase of the embryonic stem cell (ESC) cell cycle and suppress differentiation induced by let-7. Here, we evaluated the role of the retinoblastoma (Rb) family proteins in these settings. Under normal growth conditions, miR-294 promoted the rapid G1-S transition independent of the Rb family. In contrast, miR-294 suppressed the further accumulation of cells in G1 in response to nutrient deprivation and cell-cell contact in an Rb-dependent fashion. We uncovered five additional miRNAs (miR-26a, miR-99b, miR-193, miR-199a-5p, and miR-218) that silenced ESC self-renewal in the absence of other miRNAs, all of which were antagonized by miR-294 and miR-302. Four of the six differentiation-inducing miRNAs induced an Rb-dependent G1 accumulation. However, all six still silenced self-renewal in the absence of the Rb proteins. These results show that the miR-294/miR-302 family acts through Rb-dependent and -independent pathways to regulate the G1 restriction point and the silencing of self-renewal, respectively.
