The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation

doi:10.1073/pnas.0706963104

The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation

*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”, Piazzale Aldo Moro 5, 00185 Rome, Italy; and
^†Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy

Edited by Michael Rosbash, Brandeis University, Waltham, MA, and approved October 25, 2007 (received for review July 25, 2007)

Abstract

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.

Footnotes

^¶To whom correspondence should be addressed. E-mail: irene.bozzoni{at}uniroma1.it
Author contributions: A.R. and M.B. contributed equally to this work; I.B. designed research; A.R., M.B., A.S., O.S., F.G.D.A., M.M., and A.F. performed research; A.S., O.S., F.G.D.A., B.M., A.G., and C.P. contributed new reagents/analytic tools; A.R., M.B., A.F., C.P., and I.B. analyzed data; and I.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706963104/DC1.