Department of Physics and FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA.
Biophys J. 2013 Apr 16;104(8):1773-82. doi: 10.1016/j.bpj.2013.02.020.
Small regulatory RNAs are central players in the regulation of many cellular processes across all kingdoms of life. Experiments in mouse and human have shown that a typical small RNA may regulate the expression of many different genes, suggesting that small RNAs act as global regulators. It is noted though that most targets respond only weakly to the presence of the small RNA. At the same time, evidence in bacteria and animals suggest that the phenotypes associated with small RNA mutants are only due to a few of their targets. Here we assume that targets regulated by a small RNA to control function is in fact small, and propose that the role of the many other weak targets is to confer robustness to the regulation of these few principal targets. Through mathematical modeling we show that auxiliary targets may significantly buffer both number and kinetic fluctuations of the principal targets, with only minor slowdown in the kinetics of response. Analysis of genomic data suggests that auxiliary targets experience a nonspecific evolutionary pressure, playing a role at the system level. Our work is of importance for studies on small RNA functions, and impacts on the understanding of small RNA evolution.
小调控 RNA 是生命各领域中许多细胞过程调控的核心参与者。在小鼠和人类中的实验表明，一个典型的小 RNA 可能调控许多不同基因的表达，这表明小 RNA 作为全局调控因子发挥作用。然而需要注意的是，大多数靶标对小 RNA 的存在仅表现出微弱的反应。同时，细菌和动物中的证据表明，与小 RNA 突变体相关的表型仅归因于它们的少数几个靶标。在这里，我们假设受小 RNA 调控以控制功能的靶标实际上很小，并提出其他许多弱靶标的作用是为这些少数主要靶标提供调控的稳健性。通过数学建模，我们表明辅助靶标可以显著缓冲主要靶标的数量和动力学波动，而对反应动力学的影响很小。对基因组数据的分析表明，辅助靶标经历了一种非特异性的进化压力，在系统水平上发挥作用。我们的工作对于小 RNA 功能的研究以及对小 RNA 进化的理解具有重要意义。
