Resource Limitations Lead to Hidden Interactions in Gene Networks

Protein production in gene networks relies on the availability of resources necessary for transcription and translation, which are found in cells in limited amount. As various genes in a gene network compete for a common pool of resources, including RNA polymerase and ribosomes, a hidden layer of interactions among genetic circuits arises. In this work, we develop a general modeling framework using deterministic reaction rate equations to account for these interactions. We verified the model with a two-stage activation cascade and a one-stage repression circuit in experiments with E coli. Resource limitations introduce (1) a feed-forward loop in the interaction graph of an activation cascade, which shows counterintuitive negative or biphasic steady-state responses, and (2) a positive auto-regulation in a repression circuit, which leads to bistability confirmed by hysteresis behavior.