A bacterial signaling system regulates noise to enable bet hedging

Phenotypic diversity helps populations persist in changing and often unpredictable environments. One diversity-generating strategy is for individuals to switch randomly between phenotypic states such that one subpopulation has high fitness in the present environment, and another subpopulation has high fitness in an environment that might be encountered in the future. This sort of biological bet hedging can be found in all domains of life. Here, we discuss a recently described example from the bacterium Escherichia coli. When exposed to both oxygen and trimethylamine oxide (TMAO), E. coli hedges its bets on the possibility of oxygen loss by generating high cell-to-cell variability in the expression of the TMAO respiratory system. If oxygen is rapidly depleted from the environment, only those cells that had been expressing the TMAO respiratory system at high levels can continue to grow. This particular bet-hedging scheme possesses some unusual characteristics, most notably the decoupling of gene expression noise from the mean expression level. This decoupling allows bacteria to sense oxygen and regulate the amount of variability in TMAO reductase expression (that is, to turn bet hedging on or off) without having to adjust the mean TMAO reductase expression level. In this review, we discuss the features of the TMAO signaling pathway that permit the decoupling of gene expression noise from the mean and the regulation of bet hedging. We also highlight some open questions regarding the TMAO respiratory system and its regulatory architecture that may be relevant to many signaling systems.