A MiR-142-3p/EGR2 Feedback Circuitry In Human CSF-1 Driven Differentiation of Monocytes Into Macrophages

Abstract 2366

Colony-stimulating factor-1 (CSF-1 or M-CSF) triggers the differentiation of human peripheral blood monocytes into macrophages through and integrated cytokine/transcription factors circuitry. Using microarray profiling to explore the role of microRNAs (miRNAs) in this molecular circuitry, we identified the down-regulation of miR-142-3p in human macrophages obtained from CSF-1-treated monocytes. We show that miR-142-3p is a repressor of the transcription factor EGR2 (Early Growth Response 2) through direct 3'UTR interactions. Interestingly, EGR2 binds the promoter of the pre-miR-142-3p gene to negatively regulate its expression, identifying a self-regulatory feedback loop. Enforced expression of miR-142-3p in primary human monocytes as well as decreased expression of miR-142-3p observed in monocytes from patients with a chronic myelomonocytic leukemia further assess the link between miR-142-3p and EGR2 expression in these cells. A chemical inhibition of the Src kinase family prevents the regulation loop induced by CSF-1. Thus, our study uncovers an EGR2/miR-142-3p circuitry which regulates CSF-1 driven differentiation of human monocytes into macrophages.