Growth rate controls the sensitivity of gene regulatory circuits

Abstract

Unicellular organisms adapt to their changing environments by gene regulatory switches that sense chemical cues and induce specific target genes when the inducing signal is over a critical threshold. Using mathematical modeling we here show that, because growth rate sets the dilution rate of intracellular molecules, the sensitivity of gene regulatory switches automatically couples to growth rate, in a way that can be exploited by natural selection. We confirm the modeling predictions by experimentally demonstrating that, as nutrient quality is varied, the concentration of inducer required for activating the lac operon in E. coli increases quadratically with the populations growth rate. Our theory further predicts that, when growth rate is instead modulated by translation inhibition, critical inducer levels are invariant, and we experimentally validate this prediction as well. Moreover, we establish that this growth-coupled sensitivity allows bacteria to implement concentration-dependent sugar preferences, in which a new carbon source is used only if its concentration is high enough to improve upon the current growth rate of the cells. Using microfluidics in combination with time-lapse microscopy, we validate experimentally that this strategy governs how mixtures of glucose and lactose are used in E. coli at single-cell level. Overall, growth-coupled sensitivity provides a general mechanism through which cells can mute external signals in beneficial conditions when growth is fast, and become highly sensitive to alternative nutrients or stresses when growth is slow or arrested.