A mini-circuitry comprising microRNA 223 and transcription factor NF1-A and C/EBPa regulates human granulopoiesis.

MicroRNAs play important roles in cell dif- ferentiation by acting as translational inhib- itors 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/EBPa. The two factors com- pete for binding to the miR-223 promoter: NFI-A maintains miR-223 at low levels, whereas its replacement by C/EBPa, fol- lowing retinoic acid (RA)-induced differenti- ation, upregulates miR-223 expression. The competition by C/EBPa and the granulo- cytic differentiation are favored by a nega- tive-feedback loop in which miR-223 re- presses NFI-A translation. In line with this, both RNAi against NFI-A and ectopic ex- pression of miR-223 in acute promyelocytic leukemia (APL) cells enhance differentia- tion, whereas miR-223 knockdown inhibits the differentiation response to RA. Alto- gether, our data indicate that miR-223 plays a crucial role during granulopoiesis and point to the NFI-A repression as an impor- tant molecular pathway mediating gene re- programming in this cell lineage.