Université de Strasbourg

Alexandre Smirnov

Biography - Alexandre Smirnov

Molecular Genetics, Genomics and Microbiology (GMGM), University of Strasbourg  CNRS

Alexandre Smirnov, USIAS Fellow 2020Alexandre Smirnov studied molecular biology at Moscow State University in Russia. Upon graduation with a gold medal in 2006, he worked on ribonucleic acid (RNA) localisation to human mitochondria and completed his doctoral thesis jointly at the Moscow State University and in the research unit for Molecular Genetics, Genomics and Microbiology (GMGM) at the University of Strasbourg. In 2010, he joined the group of Professor Jörg Vogel in the Institute for Molecular Infection Biology (IMIB), at the University of Würzburg, Germany. During his time there, through his work on the model enterobacterial pathogen Salmonella Typhimurium, he developed a powerful gradient profiling by sequencing (Grad-seq) approach that enables the biochemical identification of new RNA classes and global RNA-binding proteins in any organism (Smirnov et al., 2016, PNAS). One important discovery brought about by this technique is the pervasive role of the global RNA chaperone ProQ in bacterial posttranscriptional gene expression control, which significantly expanded the current knowledge of microbial RNA biology and, more particularly, of small RNA-mediated regulation.

This finding stimulated Dr. Smirnov’s increasing interest in the biological properties of such pleiotropic proteins across all domains of life, and especially in evolutionarily distant contexts. In 2014, he returned to GMGM in Strasbourg to join one of the university’s Laboratories of Excellence (LabEx) on Mitochondria-nucleus Cross-talk (MitoCross) where he works with Dr. Ivan Tarassov and Dr. Nina Entelis to develop new high-throughput approaches to study mitochondrial RNA-binding proteins and RNAs. Since 2017, he is a researcher in the French National Centre for Scientific Research (CNRS) and currently studies the biology and evolution of global RNA-binding proteins, noncoding RNAs and ribosome biogenesis factors (Summer et al., 2020, Nucleic Acids Research) in as diverse genetic systems as Escherichia coli and human mitochondria.

Project - Experimental evolution of an organism with devastating impairment of regulatory networks

01/12/2020 - 30/11/2022

Living organisms regulate the expression of their genes to adapt to changing environmental conditions. They do so by using a variety of mechanisms intervening at each stage, from DNA transcription to RNA and protein turnover. Regulation at the level of RNA, also known as posttranscriptional control, is particularly important as it enables fast, nuanced and complex cellular responses. It relies on noncoding RNAs and RNA-binding proteins that can both up- and downregulate the expression of target genes. Some of these proteins are very specific and interact with only few transcripts. Others are much more pleiotropic; they recognise and regulate dozens and even hundreds of cellular RNAs. Such global RNA-binding factors, henceforth called RNA-binding hubs, play essential roles in organising and empowering posttranscriptional networks in apparently all species. It is sufficient to bring to mind well-characterised examples, such as eukaryotic Argonaute proteins or the bacterial RNA chaperone Hfq to appreciate the genuine scope of hub-mediated regulation.

The functional significance of several RNA-binding hubs has been extensively studied with biochemical and genetic approaches, which revealed how they work, what they regulate, and why it is important for the cell. However, we still lack understanding of why diverse organisms throughout evolution employ such proteins to coordinate their gene expression. Are RNA-binding hubs so essential in the long run? Can a bacterium learn to thrive without them? Would their loss provoke the emergence of new regulatory or biogenesis modes?

This project aims to experimentally test the evolutionary importance of three major bacterial RNA-binding hubs, the global RNA chaperones Hfq and ProQ and the ultraconserved ribosome assembly factor YbeY, which, via different mechanisms, control a large part of the E. coli genome. To this end, the team will employ the ‘modify-and-evolve’ approach and analyse the long-term consequences of losing one of these key proteins on the well-being of bacteria. In an adaptive evolution experiment over 2,000 generations, the team will follow how an organism with essentially destroyed posttranscriptional networks finds evolutionary trajectories to restore its fitness without recurring to the missing regulator. Additionally, transposon mutagenesis will be used to better understand both the place of these RNA-binding hubs in the genetic system of E. coli and available backup and escape solutions.

The data collected in the frame of this project are unique and promise to revolutionise our view of global RNA-binding regulators as evolutionarily important units. They are expected to provide invaluable information about the evolutionary plasticity of posttranscriptional networks and ribosome biogenesis pathways, which comes from direct experimentation rather than from a comparative phylogenetic analysis. Such data are essential for the understanding of key speciation events, which often involve dramatic rewiring of regulatory networks with little change in the gene content of an organism. Given the extensive role of posttranscriptional control in performance of engineered biological circuits and manifestation of virulence traits in facultative pathogenic bacteria, this study will also benefit the fields of synthetic biology, biotechnology and medical microbiology.

Investissements d'Avenir