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Our team focused for 15 years at studying the interplay between gene expression and nuclear organization. The genome folding is mainly guided by principles of polymer physics. Various computational chromatin-polymer models have been developed, and they successfully recapitulate many features of genome organization. Nuclear organization has been revolutionized in the recent years by ground breaking concept of 1/ loop extrusion of chromatin and 2/ phase separation of nuclear domains.
1/ A key milestone in genome organization has been the discovery of highly conserved chromatin domains known as ‘topologically associated domains’ (TADs) and chromatin loops. TADs and loops are believed to play an important role in regulating gene expression, by either facilitating or inhibiting interactions between enhancer sequences and gene promoters. Cohesin complex is a key player in TAD formation. Biophysical model called loop extrusion (LE) proposes that cohesin mediates cis contact by capturing small loops and then progressively enlarge them until the process is stopped by boundaries element
2/ Phase separation is also an important organizing principle of genome organization: Most nuclear protein complexes, above a saturation threshold, has the properties to undergo homotypic rather than heterotypic interactions. Such preferential interaction drives segregation of dynamic phases, named liquid-liquid phase separation. The paradigm of phase separation is the largest nuclear body, the nucleolus, in which three types of phase are detected: Fibrillar center (FC) around rDNA, dense fibrillar components encompassing nascent rRNA, and granular components enriched in pre-ribosomal particles. Deregulation of rRNA synthesis is quickly associated with alteration of nucleolar organisation, in which each phase are reorganized.
Genomes exist in a highly organized fashion in the nucleus of eukaryotic cells. We now need to understand how cohesin activity is regulated to establish and maintain DNA loop, and how compartmentalization affects ribosome biogenesis. To achieve those goals, a trackable genetic system combined with the development of technologies allowing to visualize chromatin loops is instrumental.
By combining quantitative tools of cell biology, biochemistry and global genetic screens, we identify the molecular components that contribute to intra-nuclear architecture. We try to identify organizational principles that dictate the spatial organization of eukaryotic genomes using yeast as model system.
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biorxiv(2023)
Nature Structural & Molecular Biology (2021)
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