Abstract
A 24-hour light and dark cycle-dependent rhythmicity pervades physiological processes in virtually all living organisms including humans. These regular oscillations are caused by external cues to endogenous, independent biological time-keeping systems (clocks). The rhythm is reflected by gene expression that varies in a circadian and specific fashion in different organs and tissues and is regulated largely by dynamic epigenetic and post-transcriptional mechanisms. This leads to well-documented oscillations of specific electrolytes, hormones, metabolites, and plasma proteins in blood samples. An emerging, important class of gene regulators is short single-stranded RNA (micro-RNA, miRNA) that interferes post-transcriptionally with gene expression and thus may play a role in the circadian variation of gene expression. MiRNAs are promising biomarkers by virtue of their disease-specific tissue expression and because of their presence as stable entities in the circulation. However, no studies have addressed the putative circadian rhythmicity of circulating, cell-free miRNAs. This question is important both for using miRNAs as biological markers and for clues to miRNA function in the regulation of circadian gene expression. Here, we investigate 92 miRNAs in plasma samples from 24 young male, healthy volunteers repeatedly sampled 9 times during a 24-hour stay in a regulated environment. We demonstrate that a third (26/79) of the measurable plasma miRNAs (using RT-qPCR on a microfluidic system) exhibit a rhythmic behavior and are distributed in two main phase patterns. Some of these miRNAs weakly target known clock genes and many have strong targets in intracellular MAPK signaling pathways. These novel findings highlight the importance of considering bio-oscillations in miRNA biomarker studies and suggest the further study of a set of specific circulating miRNAs in the regulation and functioning of biological clocks.
Highlights
The levels of many biological molecules vary according to a biological rhythm, i.e., a cyclic change that roughly follows a 24-hour period
The principal circadian oscillator is found in the suprachiasmatic nucleus (SCN) of the hypothalamus
A normal 24-hour rhythm of the participants was confirmed by analyzing for melatonin that exhibited a clear rhythm (p < 0.0001) with an amplitude of 19.84 pg/ml and a nightly peak level at 03:34 h in the study samples as previously reported [32]
Summary
The levels of many biological molecules vary according to a biological rhythm, i.e., a cyclic change that roughly follows a 24-hour period. While several miRNAs and the pre-miRNA processing machinery (Dicer RNase) are rhythmic in specific tissues such as the SCN, the eyes, and liver [8;20] and may have circadian functions [21], it is not known if any of the circulating miRNA in human blood exhibits diurnal variation It is not known if any oscillating circulating, cell-free miRNA would function as a regulator of peripheral circadian oscillators and/or is a reflection of changing miRNA levels at the sites of central and peripheral oscillators. The findings add another important intra-individual variable to consider in the design and interpretation of biomarker development studies and suggest that investigations of functional roles of these miRNAs in the regulation of biological clocks are warranted
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