Zhou Wei, Li Yan, Wang Xia, Wu Lianqi, Wang Yonghua
Bioinformatics Center, College of Life Science, Northwest A&F University, Yangling, Shaanxi, China.
BMC Syst Biol. 2011 Sep 9;5:141. doi: 10.1186/1752-0509-5-141.
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, 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.
A 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.
MiR-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.
作为一组长度为21至23个核苷酸的高度保守的小非编码RNA，微小RNA（miRNA）通过与靶mRNA中的部分或完全互补序列进行碱基配对，在转录后水平上调节基因表达，从而导致mRNA翻译的抑制和mRNA降解的加速。最近的研究表明，miRNA对于其所在骨骼肌的发育和功能至关重要。特别是，miR-206不仅被确定为骨骼肌中唯一表达的miRNA，而且在肌肉发育的调节中发挥着关键作用。尽管已知miRNA调节从发育到癌症的各种生物过程，但关于它们在哺乳动物生物钟动态调节中的作用却知之甚少。
目前通过使用希尔型项、米氏动力学类型和质量作用动力学，建立了一个详细的miR-206介导的哺乳动物生物钟系统动态模型。基于系统理论方法，该模型准确预测了生物钟的周期性和同步性。它还通过敏感性分析和参数改变来探索miR-206介导的振荡的动力学特性。我们的结果表明，miR-206是骨骼肌生物钟的重要调节因子，因此通过研究miR-206可以了解其对生物钟调节的主要特征。这些过程的模拟显示，通过miR-206介导的控制，振荡的幅度和频率可以显著改变。
MiR-206对哺乳动物生物钟的动态机制具有深远影响，通过控制幅度以及控制或改变频率来影响基因表达水平，并干扰基因产生或传递的时间顺序。这无疑揭示了转录后水平上调节生物钟的新机制，并为骨骼肌的正常发育以及诸如衰老、慢性疾病和癌症等病理状况提供了重要见解。
