Extrinsic noise driven phenotype switching in a self-regulating gene

Due to inherent noise in intracellular networks cellular decisions can be random, so genetically identical cells can display different phenotypic behavior even in identical environments. Most previous work in understanding the decision-making process has focused on the role of intrinsic noise in these systems. Yet, especially in the high copy-number regime, extrinsic noise has been shown to be much more significant. Here, using a prototypical example of a bistable self-regulating gene model, we develop a theoretical framework describing the combined effect of intrinsic and extrinsic noise on the dynamics of stochastic genetic switches. Employing our theory and Monte Carlo simulations, we show that extrinsic noise not only significantly alters the lifetimes of the phenotypic states, but can induce bistability in unexpected regions of parameter space, and may fundamentally change the escape mechanism. These results have implications for interpreting experimentally observed heterogeneity in cellular populations and for stochastic modeling of cellular decision processes.