Abstract
Cells respond to external cues by precisely coordinating multiple molecular events. Co-regulation may be established by the so-called single-input module (SIM), where a common regulator controls multiple targets. Using mathematical modeling, we compared the ability of SIM architectures to precisely coordinate protein levels despite environmental fluctuations and uncertainties in parameter values. We find that post-transcriptional co-regulation as exemplified by bacterial small RNAs (sRNAs) is particularly robust: sRNA-mediated regulation establishes highly synchronous gene expression thresholds for all mRNA targets without a need for fine-tuning of kinetic parameters. Our analyses reveal that the non-catalytic nature of sRNA action is essential for robust gene expression synchronization, and that sRNA sequestration effects underlie coupling of multiple mRNA pools. This principle also operates in the temporal regime, implying that sRNAs could robustly coordinate the kinetics of mRNA induction as well. Moreover, we observe that multi-target regulation by a small RNA can strongly enhance ultrasensitivity in mRNA expression when compared to the single-target case. Our findings may explain why bacterial small RNAs frequently coordinate all-or-none responses to cellular stress.
Highlights
Since their discovery more than thirty years ago, it has become clear that small RNAs play a crucial role in regulating gene expression. sRNAs downregulate gene expression posttranscriptionally by pairing with target mRNAs through base complementarity
We show that post-transcriptional co-regulation of two mRNAs by a shared sRNA is parameter-insensitive, and strongly promotes synexpression without a need for parameter fine-tuning
We numerically confirmed that similar conclusions hold true for the case where more than two mRNAs are strongly regulated by a shared sRNA
Summary
Since their discovery more than thirty years ago, it has become clear that small RNAs (sRNAs) play a crucial role in regulating gene expression. sRNAs downregulate gene expression posttranscriptionally by pairing with target mRNAs through base complementarity. Model-based analyses revealed that sRNAs binding their targets with sufficiently high affinity can establish a threshold-linear gene expression response at steady state [9]: the stoichiometric nature of sRNA action ensures that mRNA translation is almost completely suppressed as long as the sRNA concentration exceeds that of the mRNA (sub-threshold regime).
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