An Intermediate Pluripotent State Controlled by MicroRNAs Is Required for the Naive-to-Primed Stem Cell Transition

Publication date: Available online 24 May 2018
Source:Cell Stem Cell
Author(s): Peng Du, Mehdi Pirouz, Jiho Choi, Aaron J. Huebner, Kendell Clement, Alexander Meissner, Konrad Hochedlinger, Richard I. Gregory
The embryonic stem cell (ESC) transition from naive to primed pluripotency is marked by major changes in cellular properties and developmental potential. ISY1 regulates microRNA (miRNA) biogenesis, yet its role and relevance to ESC biology remain unknown. Here, we find that highly dynamic ISY1 expression during the naive-to-primed ESC transition defines a specific phase of "poised" pluripotency characterized by distinct miRNA and mRNA transcriptomes and widespread poised cell contribution to mouse chimeras. Loss- and gain-of-function experiments reveal that ISY1 promotes exit from the naive state and is necessary and sufficient to induce and maintain poised pluripotency, and that persistent ISY1 overexpression inhibits the transition from the naive to the primed state. We identify a large subset of ISY1-dependent miRNAs that can rescue the inability of miRNA-deficient ESCs to establish the poised state and transition to the primed state. Thus, dynamic ISY1 regulates poised pluripotency through miRNAs to control ESC fate.

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Teaser

Du et al. identify an intermediate "poised" pluripotent state characterized by specific mRNA and miRNA transcriptomes and the ability to contribute to mouse chimeras. ISY1-mediated miRNA regulation is necessary and sufficient for establishing poised pluripotency required for the naive-primed transition, providing an explanation for the early embryonic lethality of global miRNA deficiency.


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