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Diversity of chromosome loops in the budding yeast Saccharomyces cerevisiae
Chromosomes are the physical carriers of genetic information. The genome of the model organism budding yeast Saccharomyces cerevisiae (also used for its ability to ferment bread or beer) consists in 16 chromosomes. The precise spatial organization of these macromolecules is crucial for the proper execution of biological processes such as gene expression, replication or chromosome segregation.
Thanks to improvement in experimental protocols and computational methods, we recently and unexpectedly observed the presence of long-range loops in conditions other than metaphase. Interestingly, these loops seem independent of cohesin (unpublished data). The objective of the present project is to identify the biological significance of these loops and the molecular factors that regulate their formation. Preliminary results suggest that transcription process is involved suggesting a potential interplay between gene expression and long-range chromosome folding.
The project will use different experimental technologies that are used daily in the laboratory, including contact technologies such as Hi-C (Lieberman-Aiden et al. Science 2009). This technique is based on the capture and high throughput sequencing of DNA fragments that are close to each other in nucleus of a population of cells, and allows access to spatial structures at multiple scales. This project will build on the genetic power of S. cerevisiae using several mutants that have been well characterized in recent decades and are already present in the community.
Various computational techniques will be used like algorithms of pattern detection (https://github.com/koszullab/chromosight) or machine learning. The computer part will also include molecular dynamics simulations of polymers, tools already developed in the laboratory that will help to understand and interpret the experimental data generated. They will consist in the design of various toy models involving simple systems with controlled ingredients such as loop extrusion mechanisms (Fudenberg et al., Cell reports 2016), attachment of chromosomes to the nuclear envelope, etc.
All of the techniques and tools used in the project, both experimental and computational, are already in place and mastered in the laboratory, there is no technical development. The student will therefore be able to devote himself to new hypotheses and biological concepts.
This thesis will be supervised by Axel Cournac and benefits from a three-year ANR JCJC funding.