Exploring dynamic regulation by RNAs – Kinebiotics

Rapid adaptation to environmental changes is a key requirement for all living organisms. In the last decades, regulatory RNAs have emerged as tremendous players in such adaptative responses by controlling gene expression. In Escherichia coli and other bacteria, small regulatory RNAs (sRNAs) were shown to play crucial roles in a wide variety of pathways, such as stress response and control of metabolism, up to promoting antibiotic resistance. While the molecular mechanisms of action of sRNAs are increasingly understood, an important question remains as to the specific properties of RNA regulation and their advantage in respect to proteinaceous regulators such as transcription factors. Due to their rapid synthesis and action, sRNAs have been proposed to allow a fast and dynamic control of gene expression that is crucial to adapt to sudden environmental changes. However, kinetics aspects of gene regulation by sRNAs and their consequences on cell physiology are still insufficiently documented, mainly because of technical difficulties to directly observe sRNA regulation and their phenotypic consequences in vivo and in real time.
In this ever-rising field, we recently made the key observation that, in response to iron starvation, the sRNA RyhB triggers Escherichia coli phenotypic resistance to a major class of antibiotics. This phenotype is due to the regulation by RyhB of a life essential process, Fe-S cluster biogenesis. Strikingly, we newly found that two other sRNAs, OxyS and FnrS, control Fe-S cluster biogenesis in stress conditions encountered during the infectious process, oxidative stress and anaerobic conditions, respectively.
Thanks to our previous work and numerous solid data gathered by our consortium, we propose that regulation of Fe-S clusters biogenesis by this sRNA triad is essentially dynamic and serves to accelerate and provide a rapid adaptation to stress conditions. In this way, dynamic regulation by sRNAs will profoundly affect cell physiology up to modifying bacterial antibiotics resistance.
In addition to revealing new regulators of Fe-S clusters biogenesis, the Kinebiotics project directly addresses the important question of the dynamics of sRNA regulation and their consequences on cell physiology. To tackle this question, the Kinebiotics project takes advantage of the multiple expertise of our partnership to build an integrated and multidisciplinary approach. The project combines the extraordinary genetic amenability of E. coli, robust molecular biology approaches, cutting edge microfluidic characterization and powerful mathematical formalism.
Altogether, the Kinebiotics project will provide an unprecedented view on how sRNAs modulate gene expression during stress directly correlated with their effect on cell physiology. While challenging, our goal has a high breakthrough potential beyond the microbiology field as it will make a pivotal impact in the understanding of sRNA functions applicable to all living systems.