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

Nature. 2010 Feb 4;463(7281):621-6. doi: 10.1038/nature08725. Epub 2010 Jan 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Cell Dedifferentiation / genetics
  • Cell Lineage / genetics
  • Cell Proliferation*
  • Cellular Reprogramming / genetics
  • Computational Biology
  • DNA-Binding Proteins / genetics
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • Gene Silencing
  • Genes, myc / genetics
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Open Reading Frames / genetics
  • Proteins / genetics
  • RNA-Binding Proteins / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • Dgcr8 protein, mouse
  • Lin-28 protein, mouse
  • MicroRNAs
  • Proteins
  • RNA-Binding Proteins
  • Sall4 protein, mouse
  • Transcription Factors
  • mirnlet7 microRNA, mouse

Associated data

  • GEO/GSE18840