Multistability and oscillations in genetic control of metabolism

Genetic control of enzyme activity drives metabolic adaptations to environmental changes, and therefore the feedback interaction between gene expression and metabolism is essential to cell fitness. In this paper we develop a new formalism to detect the equilibrium regimes of an unbranched metabolic network under transcriptional feedback from one metabolite. Our results indicate that one-to-all transcriptional feedback can induce a wide range of metabolic phenotypes, including mono-, multistability and oscillatory behavior. The analysis is based on the use of switch-like models for transcriptional control and the exploitation of the time scale separation between metabolic and genetic dynamics. For any combination of activation and repression feedback loops, we derive conditions for the emergence of a specific phenotype in terms of genetic parameters such as enzyme expression rates and regulatory thresholds. We find that metabolic oscillations can emerge under uniform thresholds and, in the case of operon-controlled networks, the analysis reveals how nutrient-induced bistability and oscillations can emerge as a consequence of the transcriptional feedback.

► We analyze the interaction between gene and metabolic networks using a hybrid model. ► Unbranched networks under one-to-all gene control can display multistability and oscillations. ► Oscillatory fluxes appear only if two key enzymes have identical regulatory thresholds. ► One-to-all feedback can generate nutrient-induced bistability and oscillations in operons.