Section: New Results

Models of carbon metabolism in bacteria

Adaptation of bacterial growth to changes in environmental conditions, such as the availability of specific carbon sources, is triggered at the molecular level by the reorganization of metabolism and gene expression: the concentration of metabolites is adjusted, as well as the concentration and activities of enzymes, the rate of metabolic reactions, the transcription and translation rates, and the stability of proteins and RNAs. This reprogramming of the bacterial cell is carried out by i) specific interactions involving regulatory proteins or RNAs that specifically respond to the change of environmental conditions and ii) global regulation involving changes in the concentration of RNA polymerase, ribosomes, and metabolite pools that globally affect the rates of transcription, translation, and degradation of all RNAs and proteins.

A quantitative description and understanding of this complex network, cutting across metabolism, gene expression, and signalling, can be accessed through mathematical modelling only. In collaboration with Andreas Kremling, professor at TU München and former visiting scientist in the IBIS project-team, Hans Geiselmann, Delphine Ropers and Hidde de Jong developed an ensemble of variants of a simple core model of carbon catabolite repression. The model variants, with two substrate assimilation pathways and four intracellular metabolites only, differ from one another in only a single aspect, each breaking the symmetry between the two pathways in a different manner. Interestingly, all model variants are able to reproduce the data from a reference diauxic growth experiment. For each of the model variants, we predicted the behaviour in two new experimental conditions. When qualitatively comparing these predictions with experimental data, a number of models could be excluded while other model variants are still not discriminable. The best-performing model variants are based on inducer inclusion and activation of enzymatic genes by a global transcription factor, but the other proposed factors may complement these well-known regulatory mechanisms. The model ensemble, which was described in a study pubmished in BMC Systems Biology this year, offers a better understanding of the variety of mechanisms that have been proposed to play a role in carbon catabolite repression, but is also useful as an educational resource for systems biology.

The same focus on the dynamics of physiological processes has shaped a project on the post-transcriptional control of carbon central metabolism in E. coli. In the framework of the PhD thesis of Manon Morin, supported by a Contrat Jeune Scientifique INRA-Inria, the collaboration of Delphine Ropers with Muriel Cocaign-Bousquet and Brice Enjalbert at INRA/INSA Toulouse has demonstrated the key role played by the post-transcriptional regulatory system CSR in growth transitions in a series of publications in the past few years (e.g., [9]). The collaboration with INRA/INSA de Toulouse is continued in the context of the PhD thesis of Thibault Etienne, funded by an INRA-Inria PhD grant, with the objective of developing models able to explain how cells coordinate their physiology and the functioning of the transcription, translation, and degradation machineries following changes in the availability of carbon sources in the environment. This work is further supported by the ANR project ECORIB accepted this year and an IXXI grant in collaboration with the ERABLE project-team (Section 7.2).