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Reference : UMR3244-OLILAN-001
Workplace : PARIS 05
Date of publication : Monday, May 04, 2020
Scientific Responsible name : M. Chunlong Chen et M. Benjamin Audit
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 September 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
DNA replication is an essential process in all living organisms. At each cell division, the activation of over 30,000 replication origins in a coordinate manner, called replication program, is essential to ensure the duplication of >6 billion base pairs of the human genome. DNA replication program changes with chromatin organization associated with cell differentiation and development. Its dysregulation can challenge genome stability and leads to mutations, cancer and many other diseases. However, the stochastic and heterogeneous nature of mammalian replication origin activation has made studying replication initiation in human cells difficult. The present PhD project aims to contribute to a single-molecule replication profiling strategy that has the power to resolve both stochasticity and heterogeneity in origin activation patterns. It will be applied to further study replication dynamics of human cells under normal growth and upon replication stress, which will allow to get new important insights in DNA replication regulation, and how replication dysregulation lead to genome instability with consequences in human diseases.
The host team has recently developed a new approach to map active human replication origins by Optical Replication Mapping (ORM) (Klein et al. BioRxiv. 2017), combining the fluorescent detection of in vivo labeled active origins over long individuals DNA molecules and their optical mapping to the genome using the recent Bionano Genomics technology. Following the acquisition by the genomics platform of the host institution of a latest Bionano Saphyr system, the project aims to make ORM become a powerful high-throughput genomic approach to study replication program at the single molecule level. The PhD candidate will be responsible for developing an image and signal analysis pipeline for extension of the method to two in vivo replication labels, allowing to identify the direction and speed of replication progression, and to map replication origin and terminus locations as well as origin firing efficiencies genome-wide. These data will allow to question the degree of cell to-cell variability among cell population and between cell types, and to investigate the role of genetic and epigenetic features in cell-type-specific replication initiation control (location, efficiency and timing). The PhD candidate will further incorporate the acquire knowledge into a quantitative model of DNA replication program with the aim to explain the replication kinetics obtained from population-based method as well as those revealed by single molecule/cell approaches and to account for cell-type-specific replication program.
This thesis will take place at the Research Center of the Institut Curie Paris 5th arrondissement under the supervision of Chunlong CHEN (Genome Replication and Genetic Instability Program) in close collaboration with Benjamin AUDIT (Laboratory of Physics, UMR5672 CNRS, ENS de Lyon) .
The UMR3244 Dynamics of genetic information: fundamental bases and cancer is a joint research unit under the Institut Curie, the National Center for Scientific Research (CNRS) and Sorbonne University in Paris. The unit director is Mr. Antonin MORILLON.
UMR3244 brings together 6 research teams which aim to better understand the maintenance mechanisms of genome integrity, such as replication, repair and recombination, as well as the role of cell cycle control mechanisms and non-coding genomic expression in the maintenance of the epigenome.
This represents 60 people including two administrative.
Constraints and risks
We are looking for a motivated PhD candidate, holding, or in the process of completing, a master degree in bioinformatics/biostatistics, physics, applied mathematics or related areas, with strong computational and statistical background. The candidate will (i) develop image and signal processing algorithms/tools to extract quantitative information about human DNA replication from high-throughput single-molecule replication profiling experiments and (ii) conduct genomic analysis as well as mathematical/computational modeling and simulations of the DNA replication program. He/she will interact with the bioinformatics, genomics and sequencing facilities of Institut Curie and benefit from close collaboration with worldwide experimental and computational biologist experts.
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