The PU.1-Regulated Long Noncoding RNA Lnc-MC Controls Human Monocyte/Macrophage Differentiation through Interaction with MicroRNA-199a-5p

Abstract

Long noncoding RNAs (lncRNAs) are emerging as important regulators in mammalian development, but little is known about their roles in monocyte/macrophage differentiation. Here we identified a long noncoding RNA MonoCyte (lnc-MC), which exhibits increased expression during monocyte/macrophage differentiation of THP-1 and HL-60 cells as well as CD34+hematopoietic stem/progenitor cells (HSPCs), and is transcriptionally activated by PU.1. Gain and loss of function assays demonstrate that lnc-MC promotes monocyte/macrophage differentiation of THP-1 cells and CD34+HSPCs. Mechanistic investigation reveals that lnc-MC acts as a competing endogenous RNA to sequester miR-199a-5p and alleviate repression on activin A receptor type 1B (ACVR1B) expression, an important regulator of monocyte/macrophage differentiation. We also noted repressive effect of miR-199a-5p on lnc-MC expression and function, but PU.1-dominant down-regulation of miR-199a-5p results in its adverse position in the reciprocal regulation between miR-199a-5p and lnc-MC. Altogether, our work uncovers that PU.1-regulated two noncoding RNAs, lnc-MC and miR-199a-5p, have opposing roles in monocyte/macrophage differentiation and during the differentiation lnc-MC further enforces PU.1's role to facilitate the process by sponging miR-199a-5p and releasing ACVR1B expression, which confers a novel regulation mechanism composed of PU.1, lnc-MC, miR-199a-5p and ACVR1B in the monocyte/macrophage differentiation.