March 10, 2016
Over the last several decades it has been increasingly recognized that stochastic processes play a central role in transcription. Though many stochastic effects have been explained, the source of transcriptional bursting (one of the most well-known sources of stochasticity) has continued to evade understanding. Recent results have pointed to mechanical feedback as the source of transcriptional bursting but a reconciliation of this perspective with preexisting views of transcriptional regulation is lacking. In this letter we present a simple phenomenological model which is able to incorporate the traditional view of gene expression within a framework with mechanical limits to transcription. Our model explains the emergence of universal properties of gene expression, wherein the lower limit of intrinsic noise necessarily rises with mean expression level.
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January 9, 2013
This paper considers the behavior of discrete and continuous mathematical models for gene expression in the presence of transcriptional/translational bursting. We treat this problem in generality with respect to the distribution of the burst size as well as the frequency of bursting, and our results are applicable to both inducible and repressible expression patterns in prokaryotes and eukaryotes. We have given numerous examples of the applicability of our results, especially...
February 27, 2016
Inside individual cells, expression of genes is stochastic across organisms ranging from bacterial to human cells. A ubiquitous feature of stochastic expression is burst-like synthesis of gene products, which drives considerable intercellular variability in protein levels across an isogenic cell population. One common mechanism by which cells control such stochasticity is negative feedback regulation, where a protein inhibits its own synthesis. For a single gene that is expre...
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Gene expression is a fundamental process in a living system. The small RNAs (sRNAs) is widely observed as a global regulator in gene expression. The inherent nonlinearity in this regulatory process together with the bursty production of messenger RNA (mRNA), sRNA and protein make the exact solution for this stochastic process intractable. This is particularly the case when quantifying the protein noise level, which has great impact on multiple cellular processes. Here we prop...
August 3, 2015
The dynamics of short-lived mRNA results in bursts of protein production in gene regulatory networks. We investigate the propagation of bursting noise between different levels of mathematical modelling, and demonstrate that conventional approaches based on diffusion approximations can fail to capture bursting noise. An alternative coarse-grained model, the so-called piecewise deterministic Markov process (PDMP), is seen to outperform the diffusion approximation in biologicall...
June 21, 2010
The intrinsic stochasticity of gene expression can lead to large variability of protein levels across a population of cells. Variability (or noise) in protein distributions can be modulated by cellular mechanisms of gene regulation; in particular, there is considerable interest in understanding the role of post-transcriptional regulation. To address this issue, we propose and analyze a stochastic model for post-transcriptional regulation of gene expression. The analytical sol...
August 21, 2020
Eukaryotic transcription generally occurs in bursts of activity lasting minutes to hours; however, state-of-the-art measurements have revealed that many of the molecular processes that underlie bursting, such as transcription factor binding to DNA, unfold on timescales of seconds. This temporal disconnect lies at the heart of a broader challenge in physical biology of predicting transcriptional outcomes and cellular decision-making from the dynamics of underlying molecular pr...
January 11, 2011
Regulation of intrinsic noise in gene expression is essential for many cellular functions. Correspondingly, there is considerable interest in understanding how different molecular mechanisms of gene expression impact variations in protein levels across a population of cells. In this work, we analyze a stochastic model of bursty gene expression which considers general waiting-time distributions governing arrival and decay of proteins. By mapping the system to models analyzed i...
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Mathematical models of gene regulatory networks are widely used to study cell fate changes and transcriptional regulation. When designing such models, it is important to accurately account for sources of stochasticity. However, doing so can be computationally expensive and analytically untractable, posing limits on the extent of our explorations and on parameter inference. Here, we explore this challenge using the example of a simple auto-negative feedback motif, in which we ...
December 30, 2006
Even under constant external conditions, the expression levels of genes fluctuate. Much emphasis has been placed on the components of this noise that are due to randomness in transcription and translation; here we analyze the role of noise associated with the inputs to transcriptional regulation, the random arrival and binding of transcription factors to their target sites along the genome. This noise sets a fundamental physical limit to the reliability of genetic control, an...
February 22, 2011
The intrinsic stochasticity of gene expression can lead to large variability in protein levels for genetically identical cells. Such variability in protein levels can arise from infrequent synthesis of mRNAs which in turn give rise to bursts of protein expression. Protein expression occurring in bursts has indeed been observed experimentally and recent studies have also found evidence for transcriptional bursting, i.e. production of mRNAs in bursts. Given that there are disti...