Abstract
Conjugative transfer of the integrative and conjugative element ICEclc in Pseudomonas requires development of a transfer competence state in stationary phase, which arises only in 3-5% of individual cells. The mechanisms controlling this bistable switch between non-active and transfer competent cells have long remained enigmatic. Using a variety of genetic tools and epistasis experiments in P. putida, we uncovered an 'upstream' cascade of three consecutive transcription factor-nodes, which controls transfer competence initiation. One of the uncovered transcription factors (named BisR) is representative for a new regulator family. Initiation activates a feedback loop, controlled by a second hitherto unrecognized heteromeric transcription factor named BisDC. Stochastic modelling and experimental data demonstrated the feedback loop to act as a scalable converter of unimodal (population-wide or 'analog') input to bistable (subpopulation-specific or 'digital') output. The feedback loop further enables prolonged production of BisDC, which ensures expression of the 'downstream' functions mediating ICE transfer competence in activated cells. Phylogenetic analyses showed that the ICEclc regulatory constellation with BisR and BisDC is widespread among Gamma- and Beta-proteobacteria, including various pathogenic strains, highlighting its evolutionary conservation and prime importance to control the behaviour of this wide family of conjugative elements.
Highlights
Biological bistability refers to the existence of two mutually exclusive stable states within a population of genetically identical individuals, leading to two distinct phenotypes or developmental programs[1]
Previous work had implied an ICEclc-located operon of three consecutive regulatory genes in control of transfer competence formation[26]
P. putida to an ICEclc-free isogenic P. putida was below detection limit, indicating that spontaneous integrative and conjugative element (ICE) activation under those conditions is negligible (Fig. 2A)
Summary
Biological bistability refers to the existence of two mutually exclusive stable states within a population of genetically identical individuals, leading to two distinct phenotypes or developmental programs[1]. The basis for bistability lies in a stochastic regulatory decision resulting in cells following one of two possible specific genetic programs that determine their phenotypic differentiation[2]. The dual lifestyle of the Pseudomonas integrative and conjugative element (ICE) ICEclc has been described as a bistable phenotype (Fig. 1A)[10]. In the majority of cells ICEclc is maintained in the integrated state, but a small proportion of cells (3-5%) in stationary phase activates the ICE transfer competence program[10,11]. ICEclc transfer competence comprises a differentiated stable state, because initiated tc cells do not transform back to the ICE-quiescent state. Tc cells divide a few times, their division is compromised by the ICE and eventually arrests completely[13,14]
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