非相干microRNA-mediated前馈环路在噪声缓冲中的作用
The role of incoherent microRNA-mediated feedforward loops in noise buffering
摘要：
MicroRNA是一类内源性非编码RNA，在植物和动物体内负调控蛋白质编码基因的表达。已知它们在若干生物过程中起重要作用，并且与转录因子一起形成复杂且高度互连的调控网络。观察该网络的结构，可以识别出一些代表性过高的基序，这些基序预计将执行重要的基本调节功能。其中，microRNA介导的前馈环发挥着特殊的作用，在该前馈环中，主转录因子调节microRNA，并与其一起调节一组靶基因。在本文中，我们通过分析和模拟表明，该模体的不连贯的版本可以耦合的目标蛋白质水平的微调与有效的噪声控制，从而赋予精度和稳定性的整体基因表达程序，特别是在上游监管机构的波动的存在下。在其他结果中，我们的模型的一个重要预测是，波动的最佳衰减与目标表达的适度抑制相一致。这一特征与预期的微调功能一致，并且与广泛类别的microRNA对其靶蛋白输出的实际影响的实验观察一致。最后，我们描述了如果microRNA介导的电路不被认为是孤立的，而是嵌入在一个更大的监管网络中，那么microRNA靶点之间的串扰对噪声缓冲效率的影响。
英文摘要：
MicroRNAs are endogenous non-coding RNAs which negatively regulate the expression of protein-coding genes in plants and animals. They are known to play an important role in several biological processes and, together with transcription factors, form a complex and highly interconnected regulatory network. Looking at the structure of this network it is possible to recognize a few overrepresented motifs which are expected to perform important elementary regulatory functions. Among them a special role is played by the microRNA-mediated feedforward loop in which a master transcription factor regulates a microRNA and, together with it, a set of target genes. In this paper we show analytically and through simulations that the incoherent version of this motif can couple the fine-tuning of a target protein level with an efficient noise control, thus conferring precision and stability to the overall gene expression program, especially in the presence of fluctuations in upstream regulators. Among the other results, a nontrivial prediction of our model is that the optimal attenuation of fluctuations coincides with a modest repression of the target expression. This feature is coherent with the expected fine-tuning function and in agreement with experimental observations of the actual impact of a wide class of microRNAs on the protein output of their targets. Finally we describe the impact on noise-buffering efficiency of the cross-talk between microRNA targets that can naturally arise if the microRNA-mediated circuit is not considered as isolated, but embedded in a larger network of regulations.
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