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Dynamic Interplay between Eukaryotic Chromosomes: Impact on Genome Stability

Final Report Summary - DICIG (Dynamic Interplay between Eukaryotic Chromosomes: Impact on Genome Stability)

The folding of chromosomes within the nuclear space is a carefully regulated process, essential to the function and propagation of DNA molecule(s) over generations. Past and recent work have revealed its importance in bacteria or eukaryotes, where regulatory mechanisms have evolved to coordinate chromosome organization with replication, segregation, and cell division, concomitantly with other DNA-related metabolic processes such as transcription. Using a combination of genetics, imaging and genomics techniques, the project DICIG was driven by questions related to the functional interplay between chromosome organization, their stability, and their propagation over generations.

Within the framework of this funding, an interdisciplinary team of scientists that included geneticists, biophysicists and mathematician worked together to reach at a better understanding of the organizational changes experienced by yeast and bacterial genomes during replication and cell cycle, and how it is being influenced by metabolism. We have notably investigated the higher-order organization of the budding yeast (Saccharomyces cerevisiae) genome throughout the cell cycle while investigating concomitantly the roles of SMC (cohesins, condensins) complexes in controlling structural transitions. We also showed that synthetic yeast chromosomes maintain similar 3D trajectories in space compared to their natural counterparts. In addition to this research in yeast, we started to address related questions in bacteria, and unveiled the higher-order organization of several bacteria genomes. We notably focused on investigating the regulatory pathways that leads to dynamic 3D rearrangements important for the replication and segregation of these chromosomes.
While investigating the functional organization of these microorganisms genomes, we concomitantly developed computational, interdisciplinary techniques aiming at improving genome sequencing and metagenomic analysis through the exploitation of chromosome physical 3D signatures. These “contact genomics” (proximity ligation) approaches have led to unexpected results and applications. They holds potential for both fundamental discoveries and biomedical applications, as they allow the investigation of the structure and balance of complex microbial communities, such as the gut microbiota, at unprecedented resolution.

Overall, our investigations throughout this ERC project have provided new insights on the remarkable diversity of genome structures in the microbial world, and led to numerous questions regarding their roles. In the continuity of our current work, the goal of the team is to pursue the exploration of the interplay between chromosome organization of microorganisms genomes and the regulation of DNA repair, segregation, and replication.