Understanding the logic of cell cycle regulation in the bacterial class of Alphaproteobacteria
Circuitry governing cell cycle progression in the gram negative class of Alphaproteobacteria shows remarkable complexity and an intricacy of negative and positive feedbacks loops. In the lab of E. Biondi two model systems are equally studied, that share most of the cell cycle regulators, but the architecture of the cell cycle networks differs. This opens crucial biological questions, such as why the two models are different in their regulatory architecture, and what are the reasons for the differences. In collaboration with Brigitte Mossé of the team MABioS headed by E. Remy , we propose a PhD project that has the ambition to model the cell cycle circuit, on the basis of the deep knowledge accumulated over the years in the Biondi lab, and to restructure the architecture of both systems, in order to recapitulate their own behaviors. To assemble chimeric modules taking inspiration from the natural ones, and to describe the global dynamics with the so called logical formalism, should give a better comprehension of the two bacterial systems of regulation.
Caulobacter crescentus, Sinorhizobium meliloti, cell cycle regulation, qualitative analysis of regulatory networks, logical formalism
We aim to model the cell cycle architectures of Caulobacter and Sinorhizobium and to apply advanced molecular tools to construct new architectures of cell cycle regulation. We will use molecular analysis tools to understand the behaviour of cell cycle architectures in time and space by a combination of -omics approaches, molecular biology and microscopy, to quantify the bacterial cell cycle progression. This dynamics and the entanglement of feedbacks loops will be modelled and studied by logical formalism.
Proposed approach (experimental / theoretical / computational)
Experimentally, the PhD candidate will quantify cell cycle regulators and (if appropriate) their phosphorylation level of the time point of cell cycle (synchronization methods are available for both systems). Transcriptomic analysis will be performed in order to understand how genes are changing expression of the cell cycle. Each module of one organism will be genetically modified in order to recapitulate the features present in the other model system. This will be achieved by cloning and the utilization of chimeric genes as previously demonstrated (Pini et al., 2013, Mol Micro).
Based on the knowledge of cell cycle architectures (Biondi et al., 2006, Nature and Pini et al., 2015, PLOS genetics), logical models will be created taking into account those modules that present clear differences. The logical formalism will lead to a qualitative dynamical analysis, based on circuits and modularity (Remy et al, Springer, Cham, 2016), with the help of mathematical tools and the computing tool GINsim.
The determination of cell cycle biological networks and their modelling with the help of the logical formalism will require a high level of entanglement of biological knowledges and mathematical tools, and a computer implementation. The biological interpretation and the predictions derived from the mathematical models are delicate steps that will need a close collaboration of supervising in biology, mathematics and informatics.
The proposed thesis is thus clearly in the heart of interdisciplinarity between biology, mathematics and informatics.
We look for a student with a molecular biology formation, preferentially with experience already in the cell cycle progression analysis. He/she should have skills in molecular biology and molecular genetics. We have the ambition to form the mathematical skills over the duration of the PhD. In particular, combinatorics, graph theory and dynamical systems will be progressively introduced and concretely applied.
Knowledge of French and English would be a plus.