INSA Lyon, Bat Pasteur, 10 rue Jean Capelle
DNA topology (or supercoiling) is a fundamental mechanism of compaction of the bacterial chromosome. The student will analyze and model the mechanisms by which it plays a role as a global and multi-scale transcriptional regulator. In contrast to usual regulation mechanisms based on transcription factors which target specific genes, DNA topology influences gene expression in a global, non-specific manner in a wide range of species. In bacteria, modifying the topology thus allows for a rapid re-programming of the expression program along the whole chromosome, for instance in response to an external stress . Accordingly, accumulating data show that gene expression is organized spatially on the chromosome following topological and architectural domains [1,2], and depends for instance on the presence and orientation of neighbor genes . These features are evolutionarily conserved and cannot be explained by current regulation models.
This computational biology study will be based on an analysis of recent high-throughput sequencing data obtained in the team on the pathogenic bacterium Dickeya dadantii as well as published data on other organisms. Depending on the student’s background, skills and preferences, it may either be centered (1) on the analysis of new high-throughput expression and DNA topology mapping data ; or (2) on the development of mathematical/biophysical models of the underlying molecular mechanisms. Since the explored regulation mechanism is based on the fundamental physical properties of the DNA double helix, it probably constitutes an important ancestral and widespread mode of regulation currently underestimated  ; the study may thus have an important fundamental impact by relating the chromosome’s physical features to its biological function.
We are looking for a highly motivated Master 2 student with a background in bioinformatics (preferred), biology, biophysics or biochemistry. The project requires general experience in programming (Python preferred); experience in the handling of biological data is preferred. Students with experimental skills are also encouraged, as experimental approaches could optionally be included as a complement in the project. A fully funded PhD position is available for September 2020 (ANR contract), as a natural follow-up of the internship.
1. X. Jiang et al., Chromosomal “Stress-Response” Domains Govern the Spatiotemporal Expression of the Bacterial Virulence Program, mBio 2015
2. J. Cevost et al., ThreaDNA : predicting DNA mechanics’ contribution to sequence selectivity of proteins along
whole genomes, Bioinformatics 2018
3. B. El Houdaigui et al., Bacterial genome architecture shapes global transcriptional regulation by DNA supercoiling, Nucleic Acids Research 2019 https://doi.org/10.1093/nar/gkz300