Modeling suggests that gene circuit architecture controls phenotypic variability in a bacterial persistence network

Area of Science:

• Microbiology
• Systems Biology
• Genetics

Background:

• Bacterial persistence is a survival strategy where a subset of cells enters dormancy, enabling survival during antibiotic treatment.
• This non-inherited trait arises from natural gene expression variations, not genetic mutations.
• Understanding regulatory mechanisms is key to controlling persistence frequency.

Purpose of the Study:

• To model the regulatory network of the Escherichia coli HipBA toxin-antitoxin system.
• To investigate the role of stochastic fluctuations versus bistability in bacterial persistence.
• To explore how gene circuit architecture influences persistence frequency.

Main Methods:

• Developed deterministic and stochastic models of the HipBA regulatory network.
• Analyzed the impact of transcriptional, translational, and degradation noise on persistence.
• Simulated alternative gene circuit designs to assess noise levels.

Main Results:

• The persistence phenotype is not driven by bistability in the HipBA network.
• Stochastic fluctuations in molecular processes (transcription, translation, degradation, complex formation) drive cells into persistence.
• Gene circuit architecture can be modified to either increase or decrease persistence frequency.

Conclusions:

• Persistence arises from stochastic fluctuations in toxin levels crossing a critical threshold.
• The regulatory topology of gene expression networks dictates the frequency of bacterial persistence.
• Gene circuit design offers a method to tune bacterial persistence, a trait potentially influenced by evolutionary selection.