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Section: New Results

Shared control of gene expression by global physiological effects and specific regulators

Gene expression is controlled by the joint effect of (1) the global physiological state of the cell, in particular the activity of the gene expression machinery, and (2) DNA-binding transcription factors and other specific regulators. While many studies have focused on networks of transcription factors, the analysis of the relative contributions of both transcription factors and global effects of the physiological state has received relatively little attention thus far.

In the framework of the PhD thesis of former IBIS member Sara Berthoumieux, we have developed a model-based approach to distinguish between these two effects using time-resolved measurements of promoter activities. We have demonstrated the strength of the approach by analyzing a circuit involved in the regulation of carbon metabolism in E. coli, consisting of two pleiotropic regulators of the cell (Crp and Fis), the gene acs encoding the enzyme acetyl-CoA synthetase (Acs), and the signaling metabolite cyclic AMP (cAMP) which activates Crp. acs is strongly expressed in the absence of glucose and is thus an excellent indicator of the transcriptional response of carbon metabolism to a growth-phase transition.

Our results show that the transcriptional response of the network is controlled by the physiological state of the cell and the signalling metabolite cAMP. The (surprising) absence of a strong regulatory effect of transcription factors suggests that they are not the main coordinators of gene expression changes during growth transitions, but rather that they complement the effect of global physiological control mechanisms. This change of perspective has important consequences for the interpretation of transcriptome data and the design of biological networks in biotechnology and synthetic biology. An article presenting the above results was published in Molecular Systems Biology this year [5] and selected as an Editor's choice in Science (http://ibis.inrialpes.fr/article1040.html ).

In the above-mentioned work, the activity of the gene expression machinery was indirectly measured, by monitoring the activity of a constitutive gene, that is, a gene whose expression does not depend on any specific regulators but only on the activity of the gene expression machinery. There exists a huge literature on the molecular mechanisms coupling the activity of the gene expression machinery to changes in the nutritional quality of the environment, but a quantitative and dynamic picture of this very complicated regulatory system is still missing. Delphine Ropers and Edith Grac as well as Nils Giordano are developing models to achieve this, from bottom-up and top-down perspectives, respectively.