A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis

Cell. 2005 Dec 2;123(5):819-31. doi: 10.1016/j.cell.2005.09.023.


MicroRNAs play important roles in cell differentiation by acting as translational inhibitors of specific target genes. Here we show that human granulocytic differentiation is controlled by a regulatory circuitry involving miR-223 and two transcriptional factors, NFI-A and C/EBPalpha. The two factors compete for binding to the miR-223 promoter: NFI-A maintains miR-223 at low levels, whereas its replacement by C/EBPalpha, following retinoic acid (RA)-induced differentiation, upregulates miR-223 expression. The competition by C/EBPalpha and the granulocytic differentiation are favored by a negative-feedback loop in which miR-223 represses NFI-A translation. In line with this, both RNAi against NFI-A and ectopic expression of miR-223 in acute promyelocytic leukemia (APL) cells enhance differentiation, whereas miR-223 knockdown inhibits the differentiation response to RA. Altogether, our data indicate that miR-223 plays a crucial role during granulopoiesis and point to the NFI-A repression as an important molecular pathway mediating gene reprogramming in this cell lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Lineage
  • Gene Expression Regulation
  • Granulocytes / drug effects
  • Granulocytes / physiology*
  • Humans
  • MicroRNAs*
  • Models, Biological
  • Myelopoiesis / physiology*
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • Tretinoin / pharmacology


  • CCAAT-Enhancer-Binding Protein-alpha
  • MicroRNAs
  • NFI Transcription Factors
  • Tretinoin