Functional characteristics of a double negative feedback loop mediated by microRNAs
Functional characteristics of a double negative feedback loop mediated by microRNAs
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DOI：
10.1007/s11571-012-9236-7
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发表时间：
2013-10-01
影响因子：
3.7
通讯作者：
Liu, Zengrong
中科院分区：
文献类型：
--
作者：
Cai, Shuiming;Zhou, Peipei;Liu, Zengrong
MicroRNA（miRNAs）是一类小的非编码RNA，在几乎所有的细胞过程中起着至关重要的作用。作为基因表达的关键转录后调节因子，miRNA主要诱导mRNA降解或翻译抑制。最近的计算和实验研究已经确定了大量涉及miRNA和转录因子（TF）的模体。在这里，我们研究了这样一个基序的功能特征，一个两节点的miRNA介导的双负反馈环（MDNFL），其中TF抑制miRNA和TF本身是负调控的miRNA。这一主题的几个例子是从文献中描述。我们提出了一个通用的计算模型MDNFL的基础上生化法规，并探讨其动力学通过使用分叉分析。我们的研究结果表明，MDNFL可以作为一个开关。这一功能特征与实验观察到的miRNAs在发育过程中的分化等命运决定中的广泛出现是一致的。重要的是，发现在TF和miRNA的相互作用下，即使没有TF的合作结合，MDNFL模型也可以表现为宽范围参数的开关。此外，我们还研究了外部噪声如何影响MDNFL的动态行为。有趣的是，我们发现当MDNFL处于稳定区时，通过选择合适的外部噪声源，MDNFL系统可以从一个稳态切换到另一个稳态，同时miRNA或蛋白质的产生显著扩增。从工程学的角度来看，这种基于噪声的基因表达开关和放大器非常容易控制。希望本文的研究结果能为miRNAs调控基因表达提供新的视角，并为实验提供进一步的指导。
MicroRNAs (miRNAs) are a class of small, noncoding RNAs that play crucial roles in almost all cellular processes. As key post-transcriptional regulators of gene expression, miRNAs mainly induce mRNA degradation or translational repression. Recently computational and experimental studies have identified an abundance of motifs involving miRNAs and transcriptional factors (TFs). Here, we study the functional characteristics of one such motif, a two-node miRNA-mediated double negative feedback loop (MDNFL) in which a TF suppresses an miRNA and the TF itself is negatively regulated by the miRNA. Several examples of this motif are described from the literature. We propose a general computational model for the MDNFL based on biochemical regulations and explore its dynamics by using bifurcation analysis. Our results show that the MDNFL can behave as a bistable switch. This functional feature is in agreement with experimental observations of the widespread appearance of miRNAs in fate decisions such as differentiation during development. Importantly, it is found that under the interplay of a TF and an miRNA, the MDNFL model can behave as switches for wide ranges of parameters even without cooperative binding of the TF. In addition, we also investigate how extrinsic noise affects dynamic behavior of the MDNFL. Interestingly, it is found that when the MDNFL is in the bistable region, by choosing the appropriate extrinsic noise source, the MDNFL system can switch from one steady state to the other and meanwhile the production of either miRNA or protein is amplified significantly. From an engineering perspective, this noise-based switch and amplifier for gene expression is very easy to control. It is hoped that the results presented here would provide a new insight on how gene expression is regulated by miRNAs and further guidance for experiments.