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ANR funded project

Blanc - SVSE 6 - Génomique, génétique, bioinformatique et biologie systémique (Blanc SVSE 6) 2013
Projet FRA-Dom

Choreography of Chromatin Domains Across Cell Types: Reshuffling Replication Profiles and Common Fragile Sites

Common fragile sites (CFSs) are megabase-long loci characterized by conventional cytogenetics as regions prone to breakage in cells submitted to replication stress. The interest in CFSs stems from their key role in promoting DNA damages and genetic alterations associated with neurological disorders, chromosome rearrangements during tumor progression, and possibly chromosome evolution across species. We recently showed that the instability of major CFSs results from their paucity in initiation events that leaves the sites incompletely replicated upon fork slowing. Various studies now show that the replication program is tissue-dependent, which accounts for our finding that the map of CFSs differs in different cell types. In addition, available data show that at least 80% of CFSs co-map with very large genes although we found no correlation between instability and transcription status. This highly recurrent association however advocates a causal role of those genes in fragility. We propose that CFS setting relies on large-scale chromatin domains shaped by the flexible association of insulators, promoters and enhancers of cognate genes. To check this hypothesis we aim to (i) map chromatin domains hosting CFS-associated genes in different cell types in which we mapped CFSs, (ii) determine whether these domains correspond to chromatin loops, (iii) search for putative boundary elements, including transcription regulators, delineating these chromatin domains and/or loops, (iv) manipulate these elements to confirm their role in setting the extent and tri-dimensional organization of chromatin domains, and to decipher their molecular function. We will address these questions by using available genome-wide datasets, a combination of cell models and new tools allowing us to direct reshuffling of chromatin domains. Together, we expect to provide in depth mechanistic insights into how the choreography of transcription regulators impacts the replication program and, in turn, CFS setting across cell types.

Partners

IC UMR 3244 CNRS, Institut Curie

 STABILITE GENETIQUE ET ONCOGENESE

ANR grant: 457 769 euros
Beginning and duration: novembre 2013 - 48 mois

 

ANR Programme: Blanc - SVSE 6 - Génomique, génétique, bioinformatique et biologie systémique (Blanc SVSE 6) 2013

Project ID: ANR-13-BSV6-0008

Project coordinator:
Madame Michelle DEBATISSE (UMR 3244 CNRS, Institut Curie)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.