Changes in Spo0A~P pulsing frequency control biofilm matrix deactivation
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Under starvation conditions, B. subtilis survives by differentiating into one of two cell types: biofilm matrix-producing cells or sporulating cells. These two cell-differentiation pathways are activated by the same phosphorylated transcription factor - Spo0A~P. Despite sharing the activation mechanism, these cell fates are mutually exclusive at the single-cell level. This decision has been shown to be controlled by the effects of growth rate on gene dosage and protein dilution in the biofilm matrix production network. In this work, we explore an alternative mechanism of growth rate-mediated control of this cell fate decision. Namely, using deterministic and stochastic modeling, we investigate how the growth-rate-dependent pulsing dynamics of Spo0A~P affect biofilm matrix deactivation and activation. Specifically, we show that the Spo0A~P pulsing frequency tunes the biofilm matrix deactivation probability without affecting the probability of biofilm matrix activation. Interestingly, we found that DNA replication is the cell cycle stage that most substantially contributes to the deactivation of biofilm matrix production. Finally, we report that the deactivation of biofilm matrix production is not primarily regulated by the effects of growth rate on gene dosage and protein dilution. Instead, it is driven by changes in the pulsing period of Spo0A~P. In summary, our findings elucidate the mechanism governing biofilm deactivation during the late stages of starvation, thereby advancing our understanding of how bacterial networks interpret dynamic transcriptional regulatory signals to control stress-response pathways.
Author Summary
Bacteria have evolved various adaptation mechanisms to survive under challenging environmental conditions. For instance, under mild starvation, B. subtilis bacteria form biofilms — communities of cells encapsulated in a protective extracellular matrix. On the other hand, these bacteria differentiate into highly resistant spores under severe starvation. Interestingly, sporulating cells are often found within biofilm communities, but they do not contribute to biofilm matrix production. This is thought to be an energy-conservation strategy, as biofilm formation is an energy-intensive process and is therefore halted before sporulation begins. Though previous work has focused on the mechanisms driving biofilm disassembly, few studies have explored the regulatory processes that B. subtilis employs to halt matrix production prior to starting sporulation. In this study, we use mathematical models to demonstrate that the temporal dynamics of the biofilm master regulator Spo0A~P control the deactivation of matrix production. Understanding the regulation of biofilm, a common lifestyle in bacteria, can lead to the development of synthetic strategies to either enhance or disrupt biofilm formation, with potential applications in medicine and industry.
