MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells

Cell. 2009 May 15;137(4):647-58. doi: 10.1016/j.cell.2009.02.038. Epub 2009 Apr 30.

Abstract

MicroRNAs (miRNAs) are posttranscriptional modulators of gene expression and play an important role in many developmental processes. We report here that expression of microRNA-145 (miR-145) is low in self-renewing human embryonic stem cells (hESCs) but highly upregulated during differentiation. We identify the pluripotency factors OCT4, SOX2, and KLF4 as direct targets of miR-145 and show that endogenous miR-145 represses the 3' untranslated regions of OCT4, SOX2, and KLF4. Increased miR-145 expression inhibits hESC self-renewal, represses expression of pluripotency genes, and induces lineage-restricted differentiation. Loss of miR-145 impairs differentiation and elevates OCT4, SOX2, and KLF4. Furthermore, we find that the miR-145 promoter is bound and repressed by OCT4 in hESCs. This work reveals a direct link between the core reprogramming factors and miR-145 and uncovers a double-negative feedback loop involving OCT4, SOX2, KLF4, and miR-145.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / metabolism
  • Cell Differentiation*
  • Cell Line
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism
  • Gene Expression Regulation, Developmental*
  • Humans
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics*
  • MicroRNAs / metabolism*
  • Octamer Transcription Factor-3 / genetics*
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / metabolism
  • SOXB1 Transcription Factors / genetics*

Substances

  • 3' Untranslated Regions
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • MIRN145 microRNA, human
  • MicroRNAs
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • SOX2 protein, human
  • SOXB1 Transcription Factors