Quantitative Characteristics of Gene Regulation by Small RNA

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Abstract
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.