Certain types of cellular differentiation are probabilistic and transient1,2,3. 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 identified4,5, 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 responses6, thereby providing an ideal mechanism for competence regulation.
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We thank U. Alon, D. Dubnau, J. Dworkin, A. Eldar, J. Ferrell, R. Kishony, B. Lazazzera, R. Losick, A. Raj, B. Shraiman, D. Sprinzak, M. Surette and members of the laboratory for comments. G.M.S. is supported by the Caltech Center for Biological Circuit Design. J.G.-O. acknowledges financial support from the Generalitat de Catalunya and the Ministerio de Educacion y Ciencia (Spain). M.B.E. acknowledges support from the Searle Scholars Program and the Burroughs Wellcome Fund CASI program.
Movie of a B. subtilis microcolony under nutrient limitation conditions, showing PcomK and PcomG activities in blue and red colors, respectively. Simultaneous activation of comK and comG during competence results in a magenta color in the only cell of the microcolony that becomes competent.
Movie of a B. subtilis microcolony under nutrient limitation conditions, showing PcomG and PcomS activities in red and green colors, respectively. comS is expressed in all cells, but only one becomes competent. The two promoter activities are negatively correlated during competence.
Movie of a microcolony of FeBy B. subtilis cells incorporating a feedback bypass, under nutrient limitation conditions. PcomG and PcomS activities are shown in red and green colors, respectively. Competence is locked on due to the feedback bypass.