Engineered Control of Genetic Variability Reveals Interplay among Quorum Sensing, Feedback Regulation, and Biochemical Noise

Stochastic fluctuations in gene expression trigger both beneficial and harmful consequences for cell behavior. Therefore, achieving a desired mean protein expression level while minimizing noise is of interest in many applications, including robust protein production systems in industrial biotechnology. Here, we consider a synthetic gene circuit combining intracellular negative feedback and cell-to-cell communication based on quorum sensing. Accounting for both intrinsic and extrinsic noise, stochastic simulations allow us to analyze the capability of the circuit to reduce noise strength as a function of its parameters. We obtain mean expression levels and noise strengths for all species under different scenarios, showing good agreement with system-wide available experimental data and noise in Escherichia coli. Our in silico experiments, validated by preliminary in vivo results, reveal significant noise attenuation in gene expression through the interplay between quorum sensing and negative feedback and highlight the differential role that they play in regard to intrinsic and extrinsic noise.