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Rasha Boulos

"Human genome segmentation into structural domains: from chromatin conformation data to nuclear functions"
When Oct 21, 2015
from 02:00 to 04:25
Where Salle des thèses, site Monod, ENS de Lyon
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The replication program of about one half of mammalian genomes is characterized by megabase-sized replication U/N-domains. These domains are bordered by master replication origins (MaOris) corresponding to ≥ 200 kb regions of open chromatin favorable for early initiation of replication and transcription. Thanks to recent high-throughput chromosome conformation capture technologies (Hi-C), 3D co-localisation frequency matrices between all genome loci are now experimentally determined. It appeared that U/N-domains were related to the organization of the genome into structural units. In this thesis, we performed a combined analysis of human Hi-C data and replication timing profiles to further explore the structure/function relationships in the nucleus. This led us to describe novel large (>3 Mb) replication timing split-U-domains also bordered by MaOris, to demonstrate that the replication wave initiated at MaOris only depends of the time during S phase and to show that chromatin folding is compatible with a 3D equilibrium in early-replicating euchromatin regions turning to a 2D equilibrium in the late-replicating heterochromatin regions associated to nuclear lamina. Representing Hi-C co-localisation matrices as structural networks and deploying graph theoretical tools, we also demonstrated that MaOris are long-range interconnected hubs in the structural network, central to the 3D organization of the genome and we developed a novel multi-scale methodology based on graph wavelets to objectively delineate structural units from Hi-C data. This work allows us to discuss the relationship between replication domains and structural units across different human cell lines. 
Alain ARNEODO, ENS Lyon, Membre
Benjamin AUDIT, ENS Lyon, Directeur de thèse
Pierre BORGNAT, ENS Lyon, Membre
Peter R. COOK, Université d’Oxford, Membre
Arach GOLDAR, CEA Paris, Membre
Romain KOSZUL, UPMC Paris, Rapporteur 
Stéphane ROBIN, INRA Paris, Rapporteur