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Abstract
Gene expression noise is not just ubiquitous but also variable, and we still do not understand some of the most elementary factors that affect it. Among them is the residence time of a transcription factor (TF) on DNA, the mean time that a DNA-bound TF remains bound. Here, we use a stochastic model of transcriptional regulation to study how residence time affects the gene expression noise that arises when a TF induces gene expression. We find that the effect of residence time on gene expression noise depends on the TF’s concentration and its affinity to DNA, which determine the level of induction of the gene. At high levels of induction, residence time has no effect on gene expression noise. However, as the level of induction decreases, short residence times reduce gene expression noise. The reason is that fast on-off TF binding dynamics prevent long periods where proteins are predominantly synthesized or degraded, which can cause excessive fluctuations in gene expression. As a consequence, short residence times can help a gene regulation system acquire information about the cellular environment it operates in. Our predictions are consistent with the observation that experimentally measured residence times are usually modest and lie between seconds to minutes.
Highlights
The regulated gene is expressed only when the binding site is bound by a transcription factor (TF), in which case the gene is transcribed into mRNA at rate k1
A high equilibrium constant is equal to a low affinity, because it means that a large concentration of TF is required to occupy 50% of binding sites
Previous theoretical and experimental work showed that gene expression noise can be modulated by the dissociation rate kd of a DNA-bound TF (Peccoud and Ycart, 1995; Raser, 2004; Iyer-Biswas et al, 2009; Skupsky et al, 2010; Grönlund et al, 2013; Kumar et al, 2015; Fujita et al, 2016; Donovan et al, 2019), but this work did not distinguish between the effects of residence time and affinity
Summary
It produces mRNA and protein molecules whose numbers fluctuate randomly Such noise is caused by stochastic molecular interactions, which include interactions between transcription factors (TFs) and DNA, and by the stochastic synthesis and degradation of molecules (Kepler and Elston, 2001; Raj and van Oudenaarden, 2009). Gene expression noise affects multiple biological processes It can promote phenotypic diversity, influence the coordination of gene expression, trigger cell differentiation, and facilitate evolutionary transitions (Kepler and Elston, 2001; Fraser and Kaern, 2009; Raj and van Oudenaarden, 2009; Eldar and Elowitz, 2010; Sanchez et al, 2013; Karig et al, 2018; Urban and Johnston, 2018). Reducing gene expression noise can increase the ability of a regulated gene to capture information about a TF’s changing concentration or activity, which is fundamental to produce an optimal cellular response to environmental change (Rhee et al, 2012)
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