Pluripotency-associated miR-290/302 family of microRNAs promote the dismantling of naive pluripotency

Cell Res. 2016 Mar;26(3):350-66. doi: 10.1038/cr.2016.2. Epub 2016 Jan 8.

Abstract

The molecular mechanism controlling the dismantling of naive pluripotency is poorly understood. Here we show that microRNAs (miRNAs) have important roles during naive to primed pluripotency transition. Dgcr8(-/-) embryonic stem cells (ESCs) failed to completely silence the naive pluripotency program, as well as to establish the primed pluripotency program during differentiation. miRNA profiling revealed that expression levels of a large number of miRNAs changed dynamically and rapidly during naive to primed pluripotency transition. Furthermore, a miRNA screen identified numerous miRNAs promoting naive to primed pluripotency transition. Unexpectedly, multiple miRNAs from miR-290 and miR-302 clusters, previously shown as pluripotency-promoting miRNAs, demonstrated the strongest effects in silencing naive pluripotency. Knockout of both miR-290 and miR-302 clusters but not either alone blocked the silencing of naive pluripotency program. Mechanistically, the miR-290/302 family of miRNAs may facilitate the exit of naive pluripotency in part by promoting the activity of MEK pathway and through directly repressing Akt1. Our study reveals miRNAs as an important class of regulators potentiating ESCs to transition from naive to primed pluripotency, and uncovers context-dependent functions of the miR-290/302 family of miRNAs at different developmental stages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Embryonic Stem Cells / enzymology
  • Embryonic Stem Cells / metabolism*
  • Gene Silencing
  • Mice
  • MicroRNAs / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Pluripotent Stem Cells / enzymology
  • Pluripotent Stem Cells / metabolism*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA-Binding Proteins / genetics

Substances

  • Dgcr8 protein, mouse
  • MIRN290 microRNA, mouse
  • MIRN302 microRNA, mouse
  • MicroRNAs
  • RNA-Binding Proteins
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase Kinases