Figure 2. Regulation of pluripotency by microRNAs.

Model for the various roles of different families of microRNAs (miRNAs) in the gene regulatory network that maintains pluripotent and differentiating cell states. Maintenance of embryonic stem (ES) cell fate depends on the activity of the ES cell-specific cell-cycle-regulating (ESCC) miRNAs, which are induced by the core pluripotency factors OCT4, Nanog, SOX2 and KLF4 or TCF3, as well as by MYC or MYCN. ESCC miRNAs trigger S phase entry by repressing negative G1–S phase regulators (for example, the serine–threonine protein kinase LATS2, the cyclin E-Cdk2 inhibitor p21 (also known as Dacapo) and retinoblastoma-like protein 2 (RBL2))⁴⁴. Key to the stabilization of either the pluripotent or the differentiated state is the antagonism between LIN28 (on in ES cells, off in differentiating cells) and let-7 (off in ES cells, on in differentiating cells). let-7 has a central role in promoting somatic differentiation by repressing multiple genes with important functions in ES cells. Other miRNAs that contribute to the suppression of pluripotent genes upon differentiation include miRNAs that repress pluripotency factors and miR-200 family members that repress the activity of Polycomb repressive complexes PRC1 and PRC2 (REFS ¹⁴⁸,¹⁶⁵,¹⁶⁶). Red boxes indicate active miRNAs; unboxed text indicates inactive genes/miRNAs; grey lines indicate inactive processes. For further details, see the main text. Figure is modified, with permission, from REF. 46 © (2010) Macmillan Publishing Ltd. All rights reserved.