Steady-state fluctuations of a genetic feedback loop: an exact solution

TL;DR

This paper provides an exact analytical solution for the steady-state fluctuations in a genetic feedback loop, revealing detailed stochastic behavior and correcting previous inaccuracies in the modeling of such systems.

Contribution

It offers the first exact solution to the master equation for a gene regulatory feedback loop involving bimolecular reactions, clarifying previous misconceptions.

Findings

Exact steady-state probability distribution derived for the feedback loop

Verification of the solution through numerical methods

Identification and correction of errors in prior models

Abstract

Genetic feedback loops in cells break detailed balance and involve bimolecular reactions; hence exact solutions revealing the nature of the stochastic fluctuations in these loops are lacking. We here consider the master equation for a gene regulatory feedback loop: a gene produces protein which then binds to the promoter of the same gene and regulates its expression. The protein degrades in its free and bound forms. This network breaks detailed balance and involves a single bimolecular reaction step. We provide an exact solution of the steady-state master equation for arbitrary values of the parameters, and present simplified solutions for a number of special cases. The full parametric dependence of the analytical non-equilibrium steady-state probability distribution is verified by direct numerical solution of the master equations. For the case where the degradation rate of bound and free protein is the same, our solution is at variance with a previous claim of an exact solution (Hornos et al, Phys. Rev. E {\bf 72}, 051907 (2005) and subsequent studies). We show explicitly that this is due to an unphysical formulation of the underlying master equation in those studies.