Regulatory mechanisms of the multi-scale effects of intrinsic and extrinsic noise in gene expression on single cells and cell populations*

Intrinsic and extrinsic noise are ubiquitous in gene expression, affecting single-cell functioning and cell-to-cell phenotypic diversity. It is thus expected that cells have evolved means to regulate the influence of these noise sources. We conjectured that the rate-limiting steps in transcription initiation, due to their sequence-dependence as well as their responsiveness to external regulation, are key regulators of this influence. Here, we provide empirical evidence that, at the single-gene level, the kinetic regulation of these rate-limiting steps influences the impact of intrinsic and extrinsic noise sources on gene expression dynamics and on the cell-to-cell variability of its product numbers. Next, we use in silico models with empirically validated parameter values to explore the multi-scale range of these effects, i.e. from single gene, to small and large-scale genetic circuits. Based on our results, we hypothesize that bacterial cells capitalize on the rate-limiting steps’ nature of transcription initiation to evolve and tune the temporal and population-level behavioral diversity of genes and gene networks.