Section: New Results

Modeling and inference of RNA degradation

The ability to rapidly respond to changing nutrient availability is crucial for E. coli to survive in many environments including the gut. Reorganization of gene expression is the first step for bacteria to adjust their metabolism accordingly. It involves fine-tuning of both transcription and mRNA stability by dedicated regulatory interactions. While transcriptional regulation has been largely studied, the role of mRNA stability during a metabolic switch is poorly understood.

This question was addressed in the framework of the PhD thesis of Manon Morin funded by an INRA-Inria grant. Using combined genome-wide transcriptome and mRNA decay analyses, Manon Morin, Delphine Ropers and colleagues from the Toulouse Biotechnology Institute (ex-LISBP, INRA/INSA Toulouse) investigated the role of mRNA stability in the response of E. coli to nutrient changes. They demonstrated that transcript stability increases along metabolic transitions representative of the carbon source fluctuations, the glucose-acetate-starvation transition [9], [10]. Most of the stabilization occurs at glucose-acetate transition when glucose is exhausted. Stabilized mRNAs remain stable during acetate consumption and carbon starvation. Meanwhile, expression of most genes is downregulated. Metabolic control analysis showed that most of gene expression regulation is driven by changes in transcription. Post-transcriptional regulations appear to be important for genes involved in bacterial response to nutrient starvation. These results have been further developed in a paper recently submitted to a biology journal.

The observation of a global stabilization of cellular mRNAs during adaptation to carbon source depletion raises questions about the regulatory mechanisms at work. Known regulators of mRNA stability such as the protein Hfq, the carbon storage regulator Csr, and several small regulatory RNAs, specifically target mRNAs. Are these regulatory mechanisms sufficient to explain the systematic adjustment of mRNA half-lives? The collaboration with Muriel Cocaign-Bousquet and colleagues from the Toulouse Biotechnology Institute has been pursued to answer these questions, in the context of the PhD thesis of Thibault Etienne, funded by an INRA-Inria PhD grant. The objective is to develop models able to explain how cells coordinate their physiology and the functioning of the degradation machinery following environmental changes. In a paper submitted this year, Thibault Etienne, Delphine Ropers and Muriel Cocaign-Bousquet investigate the possibility that competition between mRNAs for their binding to the degradation machinery is an important mechanism for the regulation of mRNA half-lives. They develop a mathematical model of mRNA degradation and assess the role of competitive effects on mRNA degradation kinetics by numerical simulation and sensitivity analysis. Competition appears to globally increase the stability of cellular mRNAs and to amplify the effect of post-transcriptional regulation. In a follow-up study, the model is currently being used to interpret large data sets corresponding to the degradation kinetics of 4254 mRNAs in E. coli cells growing in four different environmental conditions.