Expression and Rhythmic Modulation of Circulating MicroRNAs Targeting the Clock Gene Bmal1 in Mice

Abstract

MicroRNAs (miRNAs) interact with 3′ untranslated region (UTR) elements of target genes to regulate mRNA stability or translation and thus play a role in regulating many different biological processes, including circadian rhythms. However, specific miRNAs mediating the regulation of essential clock genes remain largely unknown. Because vesicles containing membrane-bound miRNAs are present in the circulatory system, we examined miRNAs predicted to target the clock gene, Bmal1, for evidence of rhythmic fluctuations in circulating levels and modulatory effects on the 3′ UTR activity of Bmal1. A number of miRNAs with Bmal1 as a predicted target were expressed in the serum of mice exposed to LD 12∶12 and of these miRNAs, miR-152 and miR-494 but not miR-142-3p were marked by diurnal oscillations with bimodal peaks in expression occurring near the middle of the day and 8 or 12 hr later during the night. Co-transfection of pre-miR over-expression constructs for miR-494 and miR-142-3p in HEK293 cells had significant effects in repressing luciferase-reported Bmal1 3′ UTR activity by as much as 60%, suggesting that these miRNAs may function as post-transcriptional modulators of Bmal1. In conjunction with previous studies implicating miRNAs as extracellular regulatory signals, our results suggest that circulating miRNAs may play a role in the regulation of the molecular clockworks in peripheral circadian oscillators.

Circulating miR-200–family micro-RNAs have altered plasma levels in patients with endometriosis and vary with blood collection time

“…We discovered that miRNA levels varied significantly with the blood sampling time, and all three miRNAs studied had lower levels in the blood samples taken in the evening, suggesting a possible impact of the circadian rhythm on miR-200 levels. Recent publications have already provided evidence that miRNAs are involved in the regulation of the circadian rhythm and, more importantly, that the level of some miRNAs is probably regulated by the circadian clock (37,38). Bioinformatics tools were used to predict miRNAs presenting putative sites for circadian transcription factors in their promoters, and the diurnal variation of miR-27b in human leukocytes was experimentally validated (37).…”

Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects

“…In the present investigation of the plasma miRNA profiles of smokers and non-smokers, the subjects were limited to men because a study had reported subtle sex differences (Ji et al, 2009), although another study reported no large sex differences in plasma miRNA expression (Chen et al, 2008), and because smoking is more prevalent in men than in women in Japan. In addition, considering the potential effects of circadian rhythm (Shende et al, 2011), we standardized the time of blood collection.…”

Future Demands Concerning the Epigenetic Relevance of Melatonin and the Circadian System in Gerontology

“…MicroRNAs were not only detected in cells, but also in exosomes. In fact, miR-152 and miR-494 have been shown to exhibit circadian rhythms in the serum [102]. This finding indicates that that the exchange of circadian information between cells and within the multioscillator system is not restricted to hormones and neurotransmitters, but also involves microRNAs released as exosomes into the blood and, presumably, other body fluids.…”