Isocost Lines Describe the Cellular Economy of Genetic Circuits

TLDR

Genetic circuits share limited transcriptional and translational resources, leading to unexpected couplings that reduce predictability. The study seeks to determine interdependencies between gene products by characterizing the resource‑allocation economy of genetic circuits. The authors constructed a library of two‑gene reporter circuits on a single plasmid, varying ribosome binding sites and copy number to probe how resources are distributed. They discover that protein concentrations from the same plasmid fall on a linear isocost line that rotates with ribosome binding site strength and shifts with plasmid copy number, allowing prediction of coupling and informing design guidelines.

Abstract

Genetic circuits in living cells share transcriptional and translational resources that are available in limited amounts. This leads to unexpected couplings among seemingly unconnected modules, which result in poorly predictable circuit behavior. In this study, we determine these interdependencies between products of different genes by characterizing the economy of how transcriptional and translational resources are allocated to the production of proteins in genetic circuits. We discover that, when expressed from the same plasmid, the combinations of attainable protein concentrations are constrained by a linear relationship, which can be interpreted as an isocost line, a concept used in microeconomics. We created a library of circuits with two reporter genes, one constitutive and the other inducible in the same plasmid, without a regulatory path between them. In agreement with the model predictions, experiments reveal that the isocost line rotates when changing the ribosome binding site strength of the inducible gene and shifts when modifying the plasmid copy number. These results demonstrate that isocost lines can be employed to predict how genetic circuits become coupled when sharing resources and provide design guidelines for minimizing the effects of such couplings.