Chromosomal Domains and DNA Replication

Group leader

During development, chromosomal domains of gene expression are progressively established concomitantly with active cell divisions. Before each division, cells have to copy their genome with a high fidelity to prevent cell death or the development of cancerous cells. This process is named DNA replication and starts at multiple specific sites (~ 100 000 in human cells) called replication origins. A spatiotemporal program controls the positioning and the timing of activation of replication origins during the S-phase of the cell cycle. Our aim is to identify molecular mechanisms involved in the establishment of this program.

To have a global vision of the replication of the human genome, we develop high through-put analyses (DNA microarrays and deep sequencing) in order to map replication origins and their timing of activation (Figure 1). Collaboration with bio-statisticians and bio-informaticians has allowed us to establish links between these maps and genomic data on chromatin structure and gene expression. We also use an avian model system (the DT40 cell line) which has the unique property to make homologous recombination with very high rates. This powerful genetic model system allows us to efficiently test hypotheses drawn from our genomic studies. We also use this model system to follow in single cell the dynamic of replication of targeted loci (Figure 2a, figure 2b).

The understanding of the pattern of duplication of eukaryotic genomes is essential. Indeed, DNA replication not only ensures genome stability but also coordinates the establishment of gene expression programs during development.