RNA-Based Regulation: Dynamics and Response to Perturbations of Competing RNAs
RNA-Based Regulation: Dynamics and Response to Perturbations of Competing RNAs
复制标题
DOI：
10.1016/j.bpj.2014.06.035
复制
发表时间：
2014-08-19
影响因子：
3.4
通讯作者：
Marinari, Enzo
中科院分区：
文献类型：
--
作者：
Figliuzzi, Matteo;De Martino, Andrea;Marinari, Enzo
通过滴定机制，微小RNA（miRNA）可以充当其共同靶标（竞争性内源RNA或ceRNA）之间有效相互作用的介体的观察提出了以下想法（即，ceRNA假说），即RNA可以在扩展的串扰网络中相互调节。这种能力可能在转录后调控中发挥重要作用，以塑造细胞的蛋白质库。最近的工作集中在串扰网络的涌现属性强调了高灵活性和选择性，可以实现平稳。另一方面，动态方面，可能对相关的时间尺度至关重要，远不清楚。我们已经进行了动态研究的ceRNA假说的转录后调控的模型。灵敏度分析显示，ceRNA串扰是动态扩展的，即，即使在稳定状态下没有串扰发生的情况下，它也可以在比实现平稳性所需的时间尺度更短的时间尺度上发生，并且可能被放大。此外，在大的情况下，类似于转染的扰动，系统可能会产生强烈的非线性，阈值响应。最后，我们表明，ceRNA效应为细胞提供了一种非常有效的方法，在必要时实现ceRNA水平的快速正向转变。这些结果表明，竞争的小RNA可能确实提供了一个基本的机制，以实现系统水平的调节作用的转录组在生理相关的时间尺度。
The observation that, through a titration mechanism, microRNAs (miRNAs) can act as mediators of effective interactions among their common targets (competing endogenous RNAs or ceRNAs) has brought forward the idea (i.e., the ceRNA hypothesis) that RNAs can regulate each other in extended cross-talk networks. Such an ability might play a major role in posttranscriptional regulation to shape a cell's protein repertoire. Recent work focusing on the emergent properties of the cross-talk networks has emphasized the high flexibility and selectivity that may be achieved at stationarity. On the other hand, dynamical aspects, possibly crucial on the relevant timescales, are far less clear. We have carried out a dynamical study of the ceRNA hypothesis on a model of posttranscriptional regulation. Sensitivity analysis shows that ceRNA cross-talk is dynamically extended, i.e., it may take place on timescales shorter than those required to achieve stationarity even in cases where no cross-talk occurs in the steady state, and is possibly amplified. In addition, in the case of large, transfection-like perturbations, the system may develop a strongly nonlinear, threshold response. Finally, we show that the ceRNA effect provides a very efficient way for a cell to achieve fast positive shifts in the level of a ceRNA when necessary. These results indicate that competition for miRNAs may indeed provide an elementary mechanism to achieve system-level regulatory effects on the transcriptome over physiologically relevant timescales.