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Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins. [ABSTRACT FROM AUTHOR]

We present a stochastic model motivated by gene expression which incorporates un-specific interactions between proteins and binding sites. We focus on characterizing the distribution of free (i.e. unbound) protein molecules in a cell. Although it cannot be expressed in a closed form, we present three different approaches to obtain it: stochastic simulation algorithms, system of ODEs and quasi-steady-state solution. Additionally we use a large-system-size scaling to derive statistical measures of approximate distribution of the amount of free protein, such as the Fano factor. Intriguingly, we report that while in the absence of or in the excess of decoy binding sites the Fano factor is equal to one (suggestive of Poissonian fluctuations), in the intermediate regimes of moderate levels of binding sites the Fano factor is greater than one (suggestive of super-Poissonian fluctuations). We support and illustrate all of our results with numerical simulations. [ABSTRACT FROM AUTHOR]

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 expressed in bursts, negative feedback can affect the burst frequency or the burst size. In order to compare these feedback types, we study a piecewise deterministic model for gene expression of a self-regulating gene. Mathematically tractable steady-state protein distributions are derived and used to compare the noise suppression abilities of the two feedbacks. Results show that in the low noise regime, both feedbacks are similar in term of their noise buffering abilities. Intriguingly, feedback in burst size outperforms the feedback in burst frequency in the high noise regime. Finally, we discuss various regulatory strategies by which cells implement feedback to control burst sizes of expressed proteins at the level of single cells. [ABSTRACT FROM AUTHOR]

Stochastic phenomena in gene regulatory networks can be modelled by the chemical master equation for gene products such as mRNA and proteins. If some of these elements are present in significantly higher amounts than the rest, or if some of the reactions between these elements are substantially faster than others, it is often possible to reduce the master equation to a simpler problem using asymptotic methods. We present examples of such a procedure and analyse the relationship between the reduced models and the original. [ABSTRACT FROM AUTHOR]