MicroRNAs function as cis- and trans-acting modulators of peripheral circadian clocks

• Published in: FEBS letters 2014-08, Vol.588 (17), p.3015-3022
• Main Authors: Shende, Vikram R., Kim, Sam-Moon, Neuendorff, Nichole, Earnest, David J.
• Format: Article
• Language: English
• Subjects: 3′-UTR; Animals; ARNTL Transcription Factors - genetics; Cell Communication; Circadian; Circadian Clocks - genetics; Clock; E-box; Endocytosis; Exocytosis; Extracellular Space - metabolism; Gene Expression Regulation - genetics; HEK293 Cells; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA-recognition element; NIH 3T3 Cells; Oscillation; Pacemaker; Period 1; Period 2
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2014.05.058

•MiR-142-3p and miR-494 repress endogenous BMAL1 levels and modulate ensemble rhythms.•MiR-142-3p is communicated between cells by vesicular trafficking.•Inhibition of vesicular trafficking disrupts miRNA communication.•Inhibition of vesicular trafficking alters ensemble clock gene rhythms.•MiRNAs may function as trans-acting signals coordinating local time among cells. Based on their extracellular expression and targeting of the clock gene Bmal1, miR-142-3p and miR-494 were analyzed for evidence of vesicle-mediated communication between cells and intracellular functional activity. Our studies demonstrate that: miR-142-3p+miR-494 overexpression decreases endogenous BMAL1 levels, increases the period of Per2 oscillations, and increases extracellular miR-142-3p/miR-494 abundance in conditioned medium; miRNA-enriched medium increases intracellular expression of miR-142-3p and represses Bmal1 3′-UTR activity in naïve cells; and inhibitors of vesicular trafficking modulate intercellular communication of these miRNAs and ensemble Per2 rhythms. Thus, miR-142-3p and miR-494 may function as cis- and trans-acting signals contributing to local temporal coordination of cell-autonomous circadian clocks.