Gene activity is determined not only by DNA sequence, but also by the dynamic three-dimensional structure of the genome. The organization of DNA in chromatin and its disposition within the nucleus play a crucial role in processes such as cell differentiation, carcinogenesis and the inheritance of epigenetic characteristics (i.e. not associated with changes in DNA sequence).

The main objective of this work package is to understand how chromosome dynamics and their interactions with specific nuclear compartments modulate gene expression, as well as chromosome replication and repair. These studies are carried out in bakers’ yeast, a unicellular fungus often used as a model organism, since it functions like a mammalian cell while being easier to manipulate.

Several projects are centred on telomeres, the physical ends of chromosomes that are comprised of a simple repeated DNA sequence associated with a special set of proteins. While their capping function protects the chromosomes, telomeres can also act as biological clocks within the cell. Telomeres shorten with each cell division, until a critical length is reached and a stop signal is delivered. However, this event is delayed in stem cells or tumour cells, due to the activity of telomerase, an enzyme that elongates these extremities.

Researchers associated with this work package, who have already deciphered key elements involved in regulating the length of telomeres, are interested in their spatial organisation as well as their temporal order of replication. Among other things, they have discovered how the interaction of telomeres with the nuclear envelope prevents the telomerase enzyme’s activity.

The cell’s nuclear pores also play an important role in modulating gene transcription, as well as the export of gene products to the cytoplasm. The scientists identified within the pores baskets to which genes can bind. The anchorage of genes to receptors located in the basket induces them to adopt a new tri-dimensional structure, which favours their activation.

Gene expression is also influenced by epigenetic mechanisms. While pursuing a project in this domain, we have unveiled a new process used by the yeast to silence certain of its genes and involving non-coding RNAs (i.e that do not code for any protein). This breakthrough may have important implications for gene regulation in higher organisms. We thus intend to pursue our investigations into the role of these molecules in gene control and chromosome stability.

The signalling pathways that regulate eukaryotic cell growth are under scrutiny as well, namely the role of the TOR protein, which integrates the input from upstream pathways and acts as a sensor. Various TOR-containing protein complexes, identified in yeast and in mammal cells, were discovered to regulate both spatial and temporal aspects of cell growth.