Abstract
BackgroundAs a group of highly conserved small non-coding RNAs with a length of 21~23 nucleotides, microRNAs (miRNAs) regulate the gene expression post-transcriptionally by base pairing with the partial or full complementary sequences in target mRNAs, thus resulting in the repression of mRNA translation and the acceleration of mRNA degradation. Recent work has revealed that miRNAs are essential for the development and functioning of the skeletal muscles where they are. In particular, miR-206 has not only been identified as the only miRNA expressed in skeletal muscles, but also exhibited crucial roles in regulation of the muscle development. Although miRNAs are known to regulate various biological processes ranging from development to cancer, much less is known about their role in the dynamic regulation of the mammalian circadian clock.ResultsA detailed dynamic model of miR-206-mediated mammalian circadian clock system was developed presently by using Hill-type terms, Michaelis-Menten type and mass action kinetics. Based on a system-theoretic approach, the model accurately predicts both the periodicity and the entrainment of the circadian clock. It also explores the dynamics properties of the oscillations mediated by miR-206 by means of sensitivity analysis and alterations of parameters. Our results show that miR-206 is an important regulator of the circadian clock in skeletal muscle, and thus by study of miR-206 the main features of its mediation on the clock may be captured. Simulations of these processes display that the amplitude and frequency of the oscillation can be significantly altered through the miR-206-mediated control.ConclusionsMiR-206 has a profound effect on the dynamic mechanism of the mammalian circadian clock, both by control of the amplitude and control or alteration of the frequency to affect the level of the gene expression and to interfere with the temporal sequence of the gene production or delivery. This undoubtedly uncovers a new mechanism for regulation of the circadian clock at a post-transcriptional level and provides important insights into the normal development as well as the pathological conditions of skeletal muscles, such as the aging, chronic disease and cancer.
Highlights
As a group of highly conserved small non-coding RNAs with a length of 21~23 nucleotides, microRNAs regulate the gene expression post-transcriptionally by base pairing with the partial or full complementary sequences in target mRNAs, resulting in the repression of mRNA translation and the acceleration of mRNA degradation
Dynamics of the pathway Recent studies showed that the molecular mechanism of circadian oscillations relies on the feedback loops of the gene expression, and is affected by the interfering of miRNAs in the circadian rhythm choreography [11]
In this work, a miR-206mediated mammalian circadian clock model was developed and the properties of the oscillations involved in the model were investigated which incorporated the main components that play roles in the circadian rhythms
Summary
As a group of highly conserved small non-coding RNAs with a length of 21~23 nucleotides, microRNAs (miRNAs) regulate the gene expression post-transcriptionally by base pairing with the partial or full complementary sequences in target mRNAs, resulting in the repression of mRNA translation and the acceleration of mRNA degradation. The mammalian circadian clock regulates many bodily functions, such as the sleep-wake cycles, the neuroendocrine levels, mental alertness, physical strength, renal and liver activity, body temperature, blood pressure, blood viscosity and the release of appropriate hormones at different times [3]. In addition to these widely well-known effects, circadian rhythms play a role in the pathogenesis and guide the optimal treatment for certain diseases including the arthritis, asthma, cancer, cardiovascular disease, diabetes, duodenal ulcers, hypercholesterolemia, and seasonal affective disorders [4,5]
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