Small RNA driven feed-forward loop: Fine-tuning of protein synthesis through sRNA mediated cross-talk

TL;DR

This paper investigates how small RNA-mediated crosstalk in a bacterial feedforward loop optimizes protein production while minimizing fluctuations, revealing a potential mechanism for efficient stress response regulation.

Contribution

It introduces a model of sRNA-driven feedforward loop showing how crosstalk enhances protein synthesis efficiency and reduces noise, a novel insight into bacterial gene regulation.

Findings

Maximum protein synthesis occurs at low RpoS-mRNA synthesis rates.

Crosstalk reduces fluctuations in target protein levels.

Optimal synthesis correlates with minimal noise in gene expression.

Abstract

Often in bacterial regulatory networks, small noncoding RNAs (sRNA) interact with several mRNA species. The competition among mRNAs for binding to the same pool of sRNA might lead to crosstalk between the mRNAs. This is similar to the competing endogenous RNA (ceRNA) effect wherein the competition to bind to the same pool of miRNA in Eukaryotes leads to miRNA mediated crosstalk resulting in subtle and complex gene regulation with stabilised gene expression. We study an sRNA-driven feedforward loop (sFFL) where the top-tier regulator, an sRNA (RprA), translationally activates the target protein (RicI) directly and also, indirectly, via up-regulation of its transcriptional activator (RpoS/sigma^s). We show that the sRNA-mediated crosstalk between the two mRNA species leads to maximum target protein synthesis for low synthesis rates of RpoS-mRNA. This indicates the possibility of an optimal target protein synthesis with efficient utilisation of RpoS-mRNA which is typically associated with various other stress response activities inside the cell. Since gene expression is inherently stochastic due to the probabilistic nature of various molecular interactions associated with it, we next quantify the fluctuations in the target protein level using generating function-based approach and stochastic simulations. The coefficient of variation that provides a measure of fluctuations in the concentration shows a minimum under conditions that also correspond to optimal target protein synthesis. This prompts us to conclude that, in sFFL, the crosstalk leads to optimal target protein synthesis with minimal noise and efficient utilisation of RpoS-mRNA.