Toward Systems Biology

May 30 - 31, June 1, 2011

Grenoble

Gene Regulatory Networks in Bacteria: From Structure to Dynamics

The regulation of gene expression is tightly interwoven with metabolism and signal transduction. A realistic view of gene regulatory networks should therefore not only include direct interactions resulting from transcription regulation, but also indirect regulatory interactions mediated by metabolic effectors and signaling molecules. Ignoring these indirect interactions during the analysis of the network dynamics may lead crucial feedback loops to be missed. We present a method for systematically deriving indirect interactions from a model of the underlying biochemical reaction network, using weak time-scale assumptions in combination with sensitivity criteria from metabolic control analysis. This approach leads to novel insights as exemplified here on the carbon assimilation network of E. coli. We show that the derived gene regulatory network is densely connected, that the signs of the indirect interactions are largely fixed by the direction of metabolic fluxes, and that a change in flux direction may invert the sign of indirect interactions. Therefore the feedback structure of the network is much more complex than usually assumed; it appears robust to changes in the kinetic properties of its components and it can be flexibly rewired when the environment changes. We show how simple qualitative models in combination with fluorescent and luminescent reporter genes can be used to explore the dynamic behavior of complex gene regulatory networks.

Hidde de Jong, INRIA Rhône-Alpes, Grenoble