Quantitative characteristics of gene regulation by small RNA.
Quantitative characteristics of gene regulation by small RNA.
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DOI：
10.1371/journal.pbio.0050229
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发表时间：
2007-09
期刊：
影响因子：
9.8
通讯作者：
Hwa T
中科院分区：
文献类型：
--
作者：
Levine E;Zhang Z;Kuhlman T;Hwa T
越来越多的小rna （sRNAs）已被证明可以调节原核生物和真核生物的关键途径。在细菌中，反式编码的sRNAs的调控主要是在复杂的应激反应的协调中发现的。sRNAs调节其靶标表达的机制是多种多样的。大多数人的共同之处是，干扰mRNA目标的翻译也可能改变功能性srna的丰度。为了了解sRNAs在基因调控中的独特作用，我们采用实验与理论相结合的定量方法研究了大肠杆菌中两种不同类型的细菌sRNAs。我们的研究结果表明，sRNA提供了一种新的基因调控模式，具有不同于蛋白质介导的基因调控的特点。这些特性包括具有可调阈值的阈值线性响应，强大的抗噪声特性，以及内置的分层串扰功能。了解srna介导的调节的这些特殊特征可能对理解srna在协调各种应激缓解途径中发挥的微妙功能至关重要。我们的研究结果也可能有助于指导合成遗传电路的设计，这些电路具有仅用蛋白质调节剂难以获得的特性。应激反应程序的激活虽然对细菌细胞在应激条件下的生存至关重要，但在能量和底物方面是昂贵的，并且对细胞的正常功能有风险。因此，压力反应受到严格调控。最近发现的一层调控涉及小RNA分子，这些小RNA分子结合其目标的mRNA转录本，抑制其翻译并促进其切割。为了了解小RNA在调控中的作用，我们在大肠杆菌中通过数学建模和定量实验相结合的方法研究了小RNA调控的定量方面。我们已经证明，当小rna的合成速率小于某个阈值时，它们可以紧密地抑制它们的靶基因，但当合成速率远远大于该阈值时，它们几乎没有作用。重要的是，阈值水平是由小RNA本身的合成速率设定的，并且可以动态调整。生物化学特性的影响——例如两个RNA分子的结合亲和力，这只能在进化的时间尺度上改变——仅限于在小RNA的不同目标之间设置层次顺序，原则上促进应激反应的全局协调。在细菌中，小rna可以在翻译水平上调节基因的表达。这种控制的许多优点包括可调的阈值响应和对生化噪声的抵抗。
An increasing number of small RNAs (sRNAs) have been shown to regulate critical pathways in prokaryotes and eukaryotes. In bacteria, regulation by trans-encoded sRNAs is predominantly found in the coordination of intricate stress responses. The mechanisms by which sRNAs modulate expression of its targets are diverse. In common to most is the possibility that interference with the translation of mRNA targets may also alter the abundance of functional sRNAs. Aiming to understand the unique role played by sRNAs in gene regulation, we studied examples from two distinct classes of bacterial sRNAs in Escherichia coli using a quantitative approach combining experiment and theory. Our results demonstrate that sRNA provides a novel mode of gene regulation, with characteristics distinct from those of protein-mediated gene regulation. These include a threshold-linear response with a tunable threshold, a robust noise resistance characteristic, and a built-in capability for hierarchical cross-talk. Knowledge of these special features of sRNA-mediated regulation may be crucial toward understanding the subtle functions that sRNAs can play in coordinating various stress-relief pathways. Our results may also help guide the design of synthetic genetic circuits that have properties difficult to attain with protein regulators alone. The activation of stress response programs, while crucial for the survival of a bacterial cell under stressful conditions, is costly in terms of energy and substrates and risky to the normal functions of the cell. Stress response is therefore tightly regulated. A recently discovered layer of regulation involves small RNA molecules, which bind the mRNA transcripts of their targets, inhibit their translation, and promote their cleavage. To understand the role that small RNA plays in regulation, we have studied the quantitative aspects of small RNA regulation by integrating mathematical modeling and quantitative experiments in Escherichia coli. We have demonstrated that small RNAs can tightly repress their target genes when their synthesis rate is smaller than some threshold, but have little or no effect when the synthesis rate is much larger than that threshold. Importantly, the threshold level is set by the synthesis rate of the small RNA itself and can be dynamically tuned. The effect of biochemical properties—such as the binding affinity of the two RNA molecules, which can only be altered on evolutionary time scales—is limited to setting a hierarchical order among different targets of a small RNA, facilitating in principle a global coordination of stress response. In bacteria, small RNAs can regulate the expression of genes at the translational level. The many advantages of this type of control include a tuneable threshold response and resistance to biochemical noise.
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