Regulated Stochasticity in a Bacterial Signaling Network Permits Tolerance to a Rapid Environmental Change

Microbial populations can maximize fitness in dynamic environments through bet hedging, a process wherein a subpopulation assumes a phenotype not optimally adapted to the present environment but well adapted to an environment likely to be encountered. Here, we show that oxygen induces fluctuating expression of the trimethylamine oxide (TMAO) respiratory system of Escherichia coli, diversifying the cell population and enabling a bet-hedging strategy that permits growth following oxygen loss. This regulation by oxygen affects the variance in gene expression but leaves the mean unchanged. We show that the oxygen-sensitive transcription factor IscR is the key regulator of variability. Oxygen causes IscR to repress expression of a TMAO-responsive signaling system, allowing stochastic effects to have a strong effect on the output of the system and resulting in heterogeneous expression of the TMAO reduction machinery. This work reveals a mechanism through which cells regulate molecular noise to enhance fitness. [Display omitted] •Variance in TMAO reductase (torCAD) expression allows bet hedging on oxygen loss•Oxygen-dependent repression of TMAO signaling genes regulates torCAD variance•A point mutation in the repressor binding site derepresses TMAO signaling genes•In the mutant, torCAD is uniformly expressed and bet hedging does not occur Environmental oxygen regulates the cell-to-cell variability of an E. coli signal transduction system that controls anaerobic respiration but leaves the population mean unchanged, thereby revealing a distinct form of bet hedging that provides a fitness advantage when oxygen availability rapidly drops.