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Multistable gene regulatory systems sustain different levels of geneexpression under identical external conditions. Such multistability is used toencode phenotypic states in processes including nutrient uptake and persistencein bacteria, fate selection in viral infection, cell cycle control, anddevelopment. Stochastic switching between different phenotypes can occur as theresult of random fluctuations in molecular copy numbers of mRNA and proteinsarising in transcription, translation, transport, and binding. However, whichcomponent of a pathway triggers such a transition is generally not known. Bylinking single-cell experiments on the lactose-uptake pathway in E. coli tomolecular simulations, we devise a general method to pinpoint the particularfluctuation driving phenotype switching and apply this method to the transitionbetween the uninduced and induced states of the lac genes. We find that thetransition to the induced state is not caused only by the single event oflac-repressor unbinding, but depends crucially on the time period over whichthe repressor remains unbound from the lac-operon. We confirm this notion instrains with a high expression level of the repressor (leading to shorterperiods over which the lac-operon remains unbound), which show a reducedswitching rate. Our techniques apply to multi-stable gene regulatory systems ingeneral and allow to identify the molecular mechanisms behind stochastictransitions in gene regulatory circuits.

What makes the lac-pathway switch: identifying the fluctuations that trigger phenotype switching in gene regulatory systems