Noise in Gene Expression Determines Cell Fate in Bacillus subtilis

Abstract

Random cell-to-cell variations in gene expression within an isogenic population can lead to transitions between alternative states of gene expression. Little is known about how these variations (noise) in natural systems affect such transitions. In Bacillus subtilis, noise in ComK, the protein that regulates competence for DNA uptake, is thought to cause cells to transition to the competent state in which genes encoding DNA uptake proteins are expressed. We demonstrate that noise in comK expression selects cells for competence and that experimental reduction of this noise decreases the number of competent cells. We also show that transitions are limited temporally by a reduction in comK transcription. These results illustrate how such stochastic transitions are regulated in a natural system and suggest that noise characteristics are subject to evolutionary forces.Variability in gene expression within a population of genetically identical cells enables those cells to maintain a diversity of phenotypes, potentially enhancing fitness (1, 2). When the underlying gene network contains regulatory positive feedback loops, individual cells can exist in different states; some cells may, for example, live in the "off" expression state of a particular gene, whereas others are in the "on" expression state (this is an example of bistable gene expression). These stochastic fluctuations in gene expression, commonly referred to as noise, have been proposed to cause transitions between these states (3-7). We apply recently developed theories of noise (8, 9) to examine how noise influences these transitions in a natural system. An example of bistable expression with associated stochastic transitions (10-16) involves the ability of the soil bacterium Bacillus subtilis to develop "competence" for DNA uptake as it enters stationary growth phase, potentially allowing bacteria to increase their fitness by incorporating new genetic material. The genes needed for competence are transcribed only in the presence of ComK, the master regulator of competence. comK expression is subject to positive autoregulation effected by the cooperative binding of ComK to its own promoter ( Fig. 1A) (21), effectively lowering the rate of ComK degradation and allowing random fluctuations in the level of ComK to occasionally cause transitions to the competent state. Cells continue to randomly transition to competence for 2 hours, by which time (T 2 ) transitions have ceased to occur (16) and the 15% of the cells that have become competent remain so until diluted into fresh growth medium ( Fig. 1C and movie S1). In this report, we ask why cells only transition to competence for a limited duration of time and investigate the source of the fluctuations that actuate the ComK feedback loop in a minority of cells.To understand why cells only transition to the competent state for ~2 hours during stationary phase, we examined the dynamics of comK expression in noncompetent cells. Because the level of ComK in noncompetent cells is very low, we used fluoresce...

Phenotype Switching and Mutations in Random Environments

“…The cells protect themselves by suspending growth. Further examples where a similar strategy has been observed include various bacteria (Maamar et al 2007;Süel et al 2007), the yeast prion (True and Lindquist 2000) and viruses (Stumpf et al 2002).…”

Pattern formation in parabolic equations containing hysteresis with diffusive thresholds

“…Recent experiments using molecular biology methods (such as those incorporating green fluorescent protein expression under the lacoperon promoter) permitted to confirm and further study the region of bi-stability of the lac-operon even when multiple input variables (TMG that acts as the inducer and glucose, for example) were used [32]. Furthermore, multi-stable gene expression and phenotype switching in varying environmental conditions have been well documented in many natural and artificially constructed biological systems [39,27,17,37,42,34,29,20,13,16,33]. These experiments were complemented by a substantial body of theoretical work that demonstrated that organisms can gain fitness by adjusting the rate of switching between phenotypes, or switching thresholds, to the law of environmental variations.…”

Bacteria determine fate by playing dice with controlled odds

“…To enhance fitness in such environments, identical cells in isogenic populations have the capacity to stochastically differentiate into various phenotypes with special attributes (1)(2)(3)(4)(5)(6)(7)(8)(9). Stochastic fate determination guarantees variability because it provides each cell with the freedom to choose its own fate.…”

“…This hedge survival strategy allows the population to continuously deploy specialized cells in anticipation of possible drastic changes in conditions. Canonical examples include transitions into competence (2)(3)(4)(5)(6)(7)(8)(9) and transitions into slow-growing persister cells (7,10). Interestingly, although each cell has the freedom to determine its own fate, the ratio between the phenotypes is adjusted to fit the encountered and anticipated conditions.…”

“…These observations imply that stochastic cell differentiations are carried out with controlled odds to fit the needs of the population as a whole. Cellular capacity to manage the odds entails means to program and regulate the noise level and means to program the effect of the noise on the gene circuit performance (4)(5)(6)(7)(8)(9)11). Several studies show that circuit architecture can encode distinct noise behaviors critical for circuit task performance (3-5, 12, 13).…”