Double-edged role of resource competition in gene expression noise and control

Despite extensive investigation demonstrating that resource competition can significantly alter the circuits' deterministic behaviors, a fundamental issue is how resource competition contributes to the gene expression noise and how the noise can be controlled. Utilizing a two-gene circuit as a prototypical system, we uncover a surprising double-edged role of resource competition in gene expression noise: the competition decreases noise through a resource constraint but generates its own type of noise which we name as ``resource competitive noise.'' Utilization of orthogonal resources enables retaining the noise reduction conferred by resource constraint while removing the added resource competitive noise. We further compare three types of negative feedback controllers: negatively competitive regulation (NCR), local, and global controllers. Both local and NCR controllers with mRNA-mediated inhibition are efficacious at reducing noise, with NCR controllers demonstrating a superior noise-reduction capability. Combining negative feedback controllers with orthogonal resources can improve the local controllers. This work provides deep insights into the origin of stochasticity in gene circuits with resource competition and guidance for developing effective noise control strategies.