An excitable gene regulatory circuit induces transient cellular differentiation

Abstract

Certain types of cellular differentiation are probabilistic and transient. In such systems individual cells can switch to an alternative state and, after some time, switch back again. In Bacillus subtilis, competence is an example of such a transiently differentiated state associated with the capability for DNA uptake from the environment. Individual genes and proteins underlying differentiation into the competent state have been identified, but it has been unclear how these genes interact dynamically in individual cells to control both spontaneous entry into competence and return to vegetative growth. Here we show that this behaviour can be understood in terms of excitability in the underlying genetic circuit. Using quantitative fluorescence time-lapse microscopy, we directly observed the activities of multiple circuit components simultaneously in individual cells, and analysed the resulting data in terms of a mathematical model. We find that an excitable core module containing positive and negative feedback loops can explain both entry into, and exit from, the competent state. We further tested this model by analysing initiation in sister cells, and by re-engineering the gene circuit to specifically block exit. Excitable dynamics driven by noise naturally generate stochastic and transient responses, thereby providing an ideal mechanism for competence regulation.

Phenotypic Diversity Using Bimodal and Unimodal Expression of Stress Response Proteins

“…This persistent population has been found in many pathogenic microbes, and has been shown to be an important contributor to antibiotic resistance (5). Similarly, under nutrient limitation, Bacillus subtilis generates phenotypic diversity resulting in normally growing cells, sporulating cells, and those that eventually become competent (6,7). Maintaining different phenotypes within the same genotype allows populations of cells to ensure variability at every generation, reducing differences in the population growth rate across environments and ensuring survival under a variety of conditions (8).…”

Signatures of gene expression noise in cellular systems

“…(23) and (24) in the main text for the noise due to transcription and promoter activation, respectively.…”

“…Thus, random fluctuations are in general detrimental for cellular systems and several regulatory mechanisms have evolved to minimize them. Only in rare cases noise can be used to drive phenotypic switching providing a non-genetic mechanism to population heterogeneity, as found for bacterial persistence against antibiotics (23) and competence for DNA uptake from the environment (24).…”

Varieties of noise: Analogical reasoning in synthetic biology

“…In their work on the response to stress of the bacteria Bacillus subtilis they drew an analogy between the excitable dynamics of lasers and neurons and the behavior of gene regulatory networks. Süel and Garcia-Ojalvo interpreted the competence state of bacteria as an excitable state, which could be entered by means of noise in the form of stochastic fluctuation in gene expression (Süel et al, 2006).…”