[HTML][HTML] A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPα regulates human granulopoiesis

F Fazi, A Rosa, A Fatica, V Gelmetti, ML De Marchis… - Cell, 2005 - cell.com
F Fazi, A Rosa, A Fatica, V Gelmetti, ML De Marchis, C Nervi, I Bozzoni
Cell, 2005cell.com
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/EBPα.
The two factors compete for binding to the miR-223 promoter: NFI-A maintains miR-223 at
low levels, whereas its replacement by C/EBPα, following retinoic acid (RA)-induced
differentiation, upregulates miR-223 expression. The competition by C/EBPα and the …
Summary
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/EBPα. The two factors compete for binding to the miR-223 promoter: NFI-A maintains miR-223 at low levels, whereas its replacement by C/EBPα, following retinoic acid (RA)-induced differentiation, upregulates miR-223 expression. The competition by C/EBPα 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.
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