Section: Research Program

Analysis of integrated metabolic and gene regulatory networks

Participants : Eugenio Cinquemani, Hidde de Jong, Thibault Etienne, Johannes Geiselmann, Stephan Lacour, Yves Markowicz, Aline Métris, Michel Page, Corinne Pinel, Delphine Ropers [Correspondent] .

The response of bacteria to changes in their environment involves responses on several different levels, from the redistribution of metabolic fluxes and the adjustment of metabolic pools to changes in gene expression. In order to fully understand the mechanisms driving the adaptive response of bacteria, as mentioned above, we need to analyze the interactions between metabolism and gene expression. While often studied in isolation, gene regulatory networks and metabolic networks are closely intertwined. Genes code for enzymes which control metabolic fluxes, while the accumulation or depletion of metabolites may affect the activity of transcription factors and thus the expression of enzyme-encoding genes.

The fundamental principles underlying the interactions between gene expressions and metabolism are far from being understood today. From a biological point of view, the problem is quite challenging, as metabolism and gene expression are dynamic processes evolving on different time-scales and governed by different types of kinetics. Moreover, gene expression and metabolism are measured by different experimental methods generating heterogeneous, and often noisy and incomplete data sets. From a modeling point of view, difficult methodological problems concerned with the reduction and calibration of complex nonlinear models need to be addressed.

Most of the work carried out within the IBIS project-team specifically addressed the analysis of integrated metabolic and gene regulatory networks in the context of E. coli carbon metabolism (Figure 4). While an enormous amount of data has accumulated on this model system, the complexity of the regulatory mechanisms and the difficulty to precisely control experimental conditions during growth transitions leave many essential questions open, such as the physiological role and the relative importance of mechanisms on different levels of regulation (transcription factors, metabolic effectors, global physiological parameters, $...$). We are interested in the elaboration of novel biological concepts and accompanying mathematical methods to grasp the nature of the interactions between metabolism and gene expression, and thus better understand the overall functioning of the system. Moreover, we have worked on the development of methods for solving what is probably the hardest problem when quantifying the interactions between metabolism and gene expression: the estimation of parameters from hetereogeneous and noisy high-throughput data. These problems are tackled in collaboration with experimental groups at Inra/INSA Toulouse and CEA Grenoble, which have complementary experimental competences (proteomics, metabolomics) and biological expertise.

Figure 4. Network of key genes, proteins, and regulatory interactions involved in the carbon assimilation network in E. coli (Baldazzi et al., PLoS Computational Biology, 6(6):e1000812, 2010). The metabolic part includes the glycolysis/gluconeogenesis pathways as well as a simplified description of the PTS system, via the phosphorylated and non-phosphorylated form of its enzymes (represented by PTSp and PTS, respectively). The pentose-phosphate pathway (PPP) is not explicitly described but we take into account that a small pool of G6P escapes the upper part of glycolysis. At the level of the global regulators the network includes the control of the DNA supercoiling level, the accumulation of the sigma factor RpoS and the Crp$·$cAMP complex, and the regulatory role exerted by the fructose repressor FruR.