The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation.
We describe a pathway by which the master transcription factor PU.1 regulates human monocyte/macrophage differentiation. This includes miR-424 and the transcriptional factor NFI-A. We show that PU.1 and these two components are interlinked in a finely tuned temporal and regulatory circuitry: PU.1 activates the transcription of miR-424, and this up-regulation is involved in stimulating monocyte differentiation through miR-424-dependent translational repression of NFI-A. In turn, the decrease in NFI-A levels is important for the activation of differentiation-specific genes such as M-CSFr. In line with these data, both RNAi against NFI-A and ectopic expression of miR-424 in precursor cells enhance monocytic differentiation, whereas the ectopic expression of NFI-A has an opposite effect. The interplay among these three components was demonstrated in myeloid cell lines as well as in human CD34+ differentiation. These data point to the important role of miR-424 and NFI-A in controlling the monocyte/macrophage differentiation program.
Institute Pasteur Cenci-Bolognetti, Department of Genetics and Molecular Biology, Institute of Molecular Biology and Pathology, and Department of Cellular Biotechnologies and Hematology, University of Rome "La Sapienza", Rome, Italy.
A
A
Rosa
M
M
Ballarino
A
A
Sorrentino
O
O
Sthandier
F G
FG
De Angelis
M
M
Marchioni
B
B
Masella
A
A
Guarini
A
A
Fatica
C
C
Peschle
I
I
Bozzoni
D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D006410:Hematopoiesis; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1
D035683:MicroRNAs; D051839:NFI Transcription Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C497592:NFIA protein, human