Abstract
Gene expression programs in living cells are highly dynamic due to spatiotemporal molecular signaling and inherent biochemical stochasticity. Here we study a mechanism based on molecule-to-molecule variability at the RNA level for the generation of bursts of protein production, which can lead to heterogeneity in a cell population. We develop a mathematical framework to show numerically and analytically that genes regulated post transcriptionally by small RNA molecules can exhibit such bursts due to different states of translation activity (on or off), mostly revealed in a regime of few molecules. We exploit this framework to compare transcriptional and post-transcriptional bursting and also to illustrate how to tune the resulting protein distribution with additional post-transcriptional regulations. Moreover, because RNA-RNA interactions are predictable with an energy model, we define the kinetic constants of on-off switching as functions of the two characteristic free-energy differences of the system, activation and formation, with a nonequilibrium scheme. Overall, post-transcriptional bursting represents a distinctive principle linking gene regulation to gene expression noise, which highlights the importance of the RNA layer beyond the simple information transfer paradigm and significantly contributes to the understanding of the intracellular processes from a first-principles perspective.
Highlights
Living organisms of ranging complexity are continuously subjected to environmental changes that force them to make decisions
For a precise understanding of how such decisions are made and how living organisms perform, we need to characterize theoretically and experimentally the mechanisms that lead to dynamic gene expression as well as how such mechanisms can be shaped by evolution [6,7]
The concentration of the small RNA (sRNA) (s) that controls the ribosomebinding site (RBS) activity is taken as an external variable, which may vary with time and fluctuate stochastically
Summary
Living organisms of ranging complexity are continuously subjected to environmental changes that force them to make decisions. With the advent of experimental techniques with single-cell resolution, several mechanisms of stochastic nature have been recognized [8,9,10,11,12] One of these mechanisms, which has been extensively studied in recent years, is transcriptional bursting [12,13,14,15,16,17]. In this work we study the dynamic expression of a gene homogenously transcribed, but with a two-state cis-regulatory region at the RNA level (the leader region) This is a quite different regulatory model with respect to previous models, as the bursting process involves ribosomes rather than polymerases, a phenomenon previously overlooked. This study serves to point out the role of regulatory RNAs in fine-tuning gene expression levels [22,23], and gene expression noise [24,25]
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