Chromosomal Domains and Replication

During development, the chromosomal domains of gene expression are structured during cell division. The selection of potential origins of replication and the moment of activation of these sites during S phase is controlled by spatial and temporal programs. In Metazoa, the molecular mechanisms that regulate these programs are not fully understood. Our major aim is to understand how the transcription and replication programs are coupled.

Genomic studies by DNA microarray have shown that the probability that a given gene will be expressed is a function of replication timing. There is a decreased probability of finding an expressed gene in the latest replicating region of the genome and an increased probability of finding an expressed gene in the earliest replicating region. One hypothesis is that transcription/replicating timing domains are defined by higher-order chromosome structures, such as boundary elements. Elements that have the capacity to organize active domains of transcription have been described. They are named insulators.

Our model system is the chicken β-globin locus and its 5' boundary, the 5'HS4 insulator. This boundary is the most well characterized in vertebrates. Genetic studies on the chicken β-globin locus will determine in situ, in its natural chromosomal context, the role of 5'HS4 in the replication of its chromosomal region. For this purpose, we are using the avian DT40 cell line, in which homologous recombination is very efficient. In a second approach, we are testing cell lines in which a transgene flanked by either wild type or mutated boundaries. In order to obtain a global view of how chromatin structure, gene expression and DNA replication are coordinated, we are also developing a genomic analysis of the program of replication with DNA microarray.  Finally, complementary studies by confocal microscopy should also enable us to  analyse how early and late chromosomal domains are compartmentalized in the nucleus. Understanding the mechanisms that govern genome duplication is a fundamental issue. Replication is important for the maintenance of their integrity and it also coordinates the establishment of gene expression programs during development.

The group is supported by the "Ligue Nationale contre le Cancer".

Selection of publications

Genomic approaches to the initiation of DNA replication and chromatin structure reveal a complex relationship.
Meisch F, Prioleau MN.
Brief Funct Genomics. 2011 Jan;10(1):30-6. Epub 2011 Jan 28.
Abstract

Interplay between DNA replication and gene expression: a harmonious coexistence.
Maric C, Prioleau MN.
Curr Opin Cell Biol. 2010 Jun;22(3):277-83. Epub 2010 Apr 2. Review.
Abstract

Genome-wide approaches to determining origin distribution.
Cadoret JC, Prioleau MN.
Chromosome Res. 2010 Jan;18(1):79-89.
Abstract

The relationship between DNA replication and human genome organization.
Necsulea A, Guillet C, Cadoret JC, Prioleau MN, Duret L.
Mol Biol Evol. 2009 Apr;26(4):729-41. Epub 2009 Jan 6.
Abstract

Genome-wide studies highlight indirect links between human replication origins and gene regulation.
J-C. Cadoret, F. Meisch, V. Hassan-Zadeh, I. Luyten, C. Guillet, L. Duret, H. Quesneville & M-N. Prioleau
Proceedings of the National Academy of Sciences of the USA (2008), October 6, 2008
Abstract

Last modified 09/ 9/2011

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