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Epigenetic regulation is novel paradigm for transcriptional control in bacteria

Principal Supervisor: Professor Marco Oggioni, Department of Genetics and Genome Sciences

Co-supervisor: Alexander N. Gorban, Department of Mathematics

PhD project title: Epigenetic regulation is novel paradigm for transcriptional control in bacteria

University of Registration: University of Leicester

Project outline:

We have identified, as part of two previous PhD projects, a novel type of phase variable epigenetic control mechanism in bacteria with impact on gene expression and important phenotypes such as capacity to cause disease. This discovery adds a new dimension to epigenetic regulation and provided the two students with high level publications at the end of their work. Phase variable switching in the target specificity of type I methylase result in a change in methylation of the bacterial genome (Manso et al., Nature Communications 2014). With recombination rates hundred times higher than other systems this mechanism does not only represent a novelty in epigenetic control, but also presents a challenge to modellers. This system is widespread in bacteria including Gram-positive bacteria responsible for foodborne infection (De Ste Croix et al., FEMS Microbiology Reviews 2017). The present PhD project is a unique opportunity to investigate this new mechanism in a wide panel of pathogenic bacteria and strains used for food production. In particular, work will aim at the elucidation of the molecular mechanism by which methylation modifies gene expression.

The work will be divided in phases. The work will start by taking advantage of a large panel of isogenic bacterial clones with distinct chromosomal methylation patterns. Such panels of clones are now available of the pathogens Streptococcus pneumoniae, Listeria monocytogenes, Enterococcus faecalis, Streptococcus suis, and for food grade bacteria of the genus Lactobacillus. Using these unique panels of isogenic bacterial clones harbouring orthologous phase variable methylation systems with distinct target specificities, the project will aim to explore in its first part those phenotypes that are influenced by changes in chromosomal methylation (Manso et al., Nature Communications 2014; De Ste Croix et al., FEMS Microbiology Reviews 2017). Construction of targeted mutants, promoter analysis, methylome analysis and gene expression profiling will be the tools to explore the molecular mechanisms at the basis of the phenotypes observed. Methodologies will include linux based bioinformatic analysis on high performance computers, construction of genetically modified bacteria and include the “omic” technologies of metabolomics by MS, expression profiling by RNAseq and methylome analysis by single molecule real-time sequencing. The molecular aspects of phase variation and the population related aspects in the microbial culture will be subjected to mathematical modelling. We plan to develop a hierarchy of kinetic models for phase variation and epigenetic transformations. The project will use the concept of “optimal complexity” and apply the modern methods of systems’ identification and as an alternative method the combination of agent-based methodology with equation-free technologies. As for the biological and bioinformatic part, the student will be offered specific training for the mathematical work.

The large portfolio of cutting edge technologies used and the interdisciplinary nature of the work are intended to provide an excellent training and solid background for a scientist able to tackle novel challenges in a wide variety of scientific settings extending over those specifically covered in the project.

The first work describing phase variable epigenetic control in bacteria was published jointly by the Departments of Genetics and Mathematics of the University of Leicester (Manso et al., 2014. Nature Communications. 5:5055).

BBSRC Strategic Research Priority: Food Security

Techniques that will be undertaken during the project:

Techniques will include bacterial culture methodologies, construction of mutants, molecular methods as PCR, real time PCR and GeneScan analysis, bioinformatic database analysis and processing of next generation sequencing data as methylome analysis, SNP detection and RNAseq analysis. In addition to work in microbial genetics the candidate will receive training in mathematical modelling. This will include the access to applied mathematics modules “Mathematical Modelling”, “Data Mining” and “Scientific Computing” as well as the advanced reading module of mathematical methods in genomics and epigenomics.

Training on for in vivo skills training in mammalian systems. Students will attend the Home Office Training Courses on Rodents modules 1-4 and then be trained in the Central Research Facility in Leicester equipped with excellent imaging and biosafety biosafety facilities for experimental infections.

Contact: Professor Marco Oggioni, University of Leicester