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Section: New Results

Systems biology

Participants : Jérémie Bourdon, Jean Coquet, Victorien Delannée, Jacques Nicolas, Anne Siegel, Nathalie Théret, Pierre Vignet.

A modeling approach to evaluate the balance between bioactivation and detoxification of MeIQx in human hepatocytes Heterocyclic aromatic amines (HAA), including MeIQx, are environmental and food contaminants that are potentially carcinogenic for humans. Using a computational approach, we developed a numerical model for MeIQx metabolism that predicts the MeIQx biotransformation into detoxification or bioactivation pathways according to the concentration of MeIQx. Our results demonstrate that CYP1A2 is a key enzyme in the system that regulates the balance between bioactivation and detoxification. This highlights the importance of complex regulations of enzyme competitions that should be taken into account in any multi-organ model [V. Delannée, A. Siegel, N. Théret] [17]

caspo: a toolbox for automated reasoning on the response of logical signaling networks families The accompanying paper of the complete family of modules introduced in the caspo software was published in 2017 (see software section for details) [A. Siegel] [22]

Identifying Functional Families of Trajectories in Biological Pathways by Soft Clustering: Application to TGF-$\beta$ Signaling At a dynamical level, in [40], reaction-based and regulatory information was transpoed in a unified formalism of enriched Petri Nets (discrete dynamical systems), namely a simplified version of guarded transitions in which we introduced temporal parameters for each transition to manage competition and cooperation between parts of the models. This allowed integrating the 137 human signaling maps from the Pathway Interaction Database (PID) into a single unified large-scale dynamic model. Simulation and model checking analyses evidence that 15,934 different sets of molecules are able to regulate 159 of TGF-$\beta$ target genes (TGF-$\beta$ is a multifunctional cytokine that regulates mammalian cell development, differentiation, and homeostasis). Further analysis of these 15,934 sets of molecules by biological experts is obviously impractical. Our study identified five clusters of sets of molecules for which enrichment analysis highlighted the over-represented molecules as well as the specific biological processes they are associated with. These results are biologically-relevant and consistent with the pleiotropic nature of TGF-$\beta$ [J. Coquet, N. Théret, O. Dameron] [25]

A Logic for checking the probabilistic steady-state properties of reaction networks. We have constructed a probabilistic analog to flux balance analysis of reaction networks to enable a formal verification of logical constrains about the stationary regime of a system by using information from experimental variances and co-variances. This is mainly based on a stationary analysis of the probabilistic dynamics relying on a Bernoulli approximation of a reaction network. The analysis requires solving non linear optimization problems [J. Bourdon, A. Siegel] [20]