Bacterial gene circuits exhibit fluctuations in the levels of regulatory proteins. It enables a subpopulation of cells to enter a transient antibiotic-resistant state, enhancing their survival. This mechanism, called bet-hedging, ensures that cells do not all exist in the same transcriptional state. This would permit the survival of the bacterial colony in case of future environmental changes. Studying bet-hedging is important for public health. The spread of infectious diseases can depend on activation of alternative genetic programmes, such as competence, general stress response, and antibiotic persistence in bacteria. The EU-funded BET-HEDGING BACTERIA project investigated the mechanisms by which bacterial cells generate alternative transcriptional states. The researchers have observed stochastic pulsing behaviour in seven alternative bacterial transcription initiation factors (sigma factors) under energy stress. Preliminary results with individual factors suggested a wide range of sigma factor pulse dynamics under stress. In particular, sigV showed bimodal activation under lysozyme stress. The simple mathematical model of sigV activation suggested that the bimodal activity for sigV under lysozyme stress can be explained by a difference in its regulation compared to sigB with frequency modulated pulsing. The anti-sigma V factor was targeted for degradation under stress, while the anti-sigma factor of sigB is being sequestered. Mathematical models demonstrated that this difference in regulation can lead to bimodality in sigV activity. In addition to the original project goals, the researchers have tested the existence of the heterogeneous activation of sigma factors in bacillus biofilms. Bacillus subtilis grows as a biofilm in the wild. The researchers have investigated whether heterogeneous expression patterns also occur in biofilms. They have found that sigB was expressed heterogeneously in biofilms and the single cell distributions of sigB activity were similar to that observed in liquid culture and in agarose. Interestingly, they also observed that highest sigB expression was at the top of the biofilm. The success of this project significantly advanced our understanding of how heterogeneous transcriptional states help bacteria to survive in a hostile environment. The hope is that the work can have long-term implications for public health.
Bet-hedging, bacterial gene circuits, antibiotic persistence, BET-HEDGING BACTERIA, sigma factors