Opposing microRNA families regulate self-renewal in mouse embryonic stem cells

Collin Melton, Robert L. Judson and Robert Blelloch ()
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Collin Melton: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Program in Biomedical Sciences,
Robert L. Judson: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Program in Biomedical Sciences,
Robert Blelloch: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, Program in Biomedical Sciences,

Nature, 2010, vol. 463, issue 7281, 621-626

Abstract: Abstract When embryonic stem cells (ESCs) differentiate, they must both silence the ESC self-renewal program and activate new tissue-specific programs. In the absence of DGCR8 (Dgcr8-/-), a protein required for microRNA (miRNA) biogenesis, mouse ESCs are unable to silence self-renewal. Here we show that the introduction of let-7 miRNAs—a family of miRNAs highly expressed in somatic cells—can suppress self-renewal in Dgcr8-/- but not wild-type ESCs. Introduction of ESC cell cycle regulating (ESCC) miRNAs into the Dgcr8-/- ESCs blocks the capacity of let-7 to suppress self-renewal. Profiling and bioinformatic analyses show that let-7 inhibits whereas ESCC miRNAs indirectly activate numerous self-renewal genes. Furthermore, inhibition of the let-7 family promotes de-differentiation of somatic cells to induced pluripotent stem cells. Together, these findings show how the ESCC and let-7 miRNAs act through common pathways to alternatively stabilize the self-renewing versus differentiated cell fates.

Date: 2010
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DOI: 10.1038/nature08725

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