Integrating Transcriptional and Allosteric Regulation in Central Metabolism of E. Coli

At any given point in time, a multitude of cellular regulation processes occur simultaneously at different molecular levels and interact with each other through various feedback mechanisms. This intricate system of interconnected networks of genes, RNAs, proteins and metabolites is primarily investigated by discovery of individual regulation processes and by characterizing particular molecular mechanisms, largely driven by novel experimental technologies such as DNA-protein interaction analyses or phosphoproteomics. So far our understanding of which regulatory processes control which cellular processes is very limited. The questions that remain elusive concern their dynamics over time or different conditions, their strength, and how they are coordinated with other processes to allow cellular behaviors such as homeostasis or dynamic adaptations.

This project aims to dissect the importance and contribution of each regulation layer in controlling metabolism of the bacterium Escherichia coli by asking at which point (“when”) each regulatory layer is operating and to what extent it regulates metabolic fluxes (“how much”). We focus on integrating the metabolite-based intracellular signals through which metabolism feeds back into the regulation layers. Specifically, we develop mechanistic models that integrate the relevant molecular processes during dynamic transitions between glycolytic and gluconeogenic carbon sources and under stress conditions, at the level of gene expression, enzyme activity and metabolite-based allosteric feedback to  transcription factors and enzymes. We aim to quantitatively recapitulate the key regulation events from the immediate metabolic response to new environmental conditions, that occur within a few seconds all the way until new steady state growth is achieved.

Mot-clé: Central metabolism, regulation, mathematical modeling, complex systems