  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.

Molecular Networks;Statistical Mechanics;Quantitative Methods