Periodic Reporting for period 1 - NPCChr (A role for nuclear pore complexes in chromatin organization during early development?)
Reporting period: 2016-03-01 to 2018-02-28
Senescent cells are cells that have stopped dividing in an irreversible manner. Interestingly cellular senescence is naturally triggered in the context of cancer, therefore constituting a antitumorigenic mechanism. On the other hand senescent cells are also secreting specific molecules, which are constitute the so-called senescence associated secretory phenotype (SASP). Paradoxically SASP can promote cellular division on neighbouring cells, angiogenesis and invasion, which are mechanisms that would lead to metastasis formation and agressive tumours. Senescence is therefore both beneficial and detrimental in the context of cancer and understanding how the SASP is regulated would allow the development of new therapeutical approaches against cancer.
Beside cell cycle arrest and SASP senescent cells also show a complete reorganization of their chromatin. The inactive heterochromatin is not stored in the nuclear periphery as it usually is in non senescent cells but forms big foci in the inner nucleus. This foci are called senescence associated heterochromatin foci (SAHF). The goal of my project was to understand how chromatin is reorganized in senescent cells and what is the role of this chromatin reorganization.
I showed that the nuclear pores, which are the complexes responsible for the exchange between the nucleus and the rest of the cells are key regulators of chromatin reorganization in senescence. I demonstrated that nuclear pores density increases drastically in senescence. This increase leads to the desattachement of heterochromatin from the nuclear periphery and the formation of SAHF. Interestingly I could show that SAHF are not necessary for cell cycle arrest but are necessary for the activation of SASP. SAHF loss resulted in an uncoupling of cell cycle arrest and SASP activation, therefore suggesting that chromatin reorganization and the formation of SAHF could represent a good therapeutical target in cancer.
The importance of global chromatin reorganization has also been questioned. For example, is it a consequence of changes in transcription or is chromatin reorganization a mechanism that can effectively modulate gene expression? Our results indicate that chromatin reorganization in OIS is key for the activation of SASP, therefore directly proving the importance of global chromatin organization in physiological processes.