A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis.
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.
Fazi
Francesco
F
Department of Histology and Medical Embryology, University of Rome La Sapienza and San Raffaele Biomedical Science Park of Rome, Via di Castel Romano 100, 00128, Rome, Italy.
Rosa
Alessandro
A
Fatica
Alessandro
A
Gelmetti
Vania
V
De Marchis
Maria Laura
ML
Nervi
Clara
C
Bozzoni
Irene
I
D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs; D008954:Models, Biological; D038042:Myelopoiesis / Q000502:physiology*; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014212:Tretinoin / Q000494:pharmacology
D022763:CCAAT-Enhancer-Binding Protein-alpha; D035683:MicroRNAs; D051839:NFI Transcription Factors; D014212:Tretinoin