MiR-294/-302 promotes proliferation, suppresses G1-S restriction point, and inhibits embryonic stem cell differentiation through separable mechanisms

• Published in: Cell reports (Cambridge) 2013-07, Vol.4 (1), p.99-109
• Main Authors: Wang, Yangming, Melton, Collin, Li, Ya-Pu, Shenoy, Archana, Zhang, Xin-Xin, Subramanyam, Deepa, Blelloch, Robert
• Format: Article
• Language: English
• ISSN: 2211-1247
• DOI: 10.1016/j.celrep.2013.05.027

The miR-294/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 (miRs-26a, -99b, -193, -199a-5p, and 218) that silenced ESC self-renewal in the absence of other miRNAs, all of which were antagonized by miR-294/302. 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.