Linking nuclear pores to chromatin organization and senescence – NPCOS

In most somatic cells, the heterochromatin accumulates at the nuclear periphery and around the nucleoli. How this global chromatin organization is established and maintained and how it participates in the regulation of gene expression is not entirely clear. Using oncogene-induced senescence (OIS) as a model, I showed that modulation of nuclear pore density can regulate heterochromatin association with the nuclear periphery, induce global chromatin reorganization and lead to activation of specific gene programs.
OIS is an irreversible arrest of the cell cycle triggered by oncogene activation, associated with increased secretion of various proteins through the senescence-associated secretory phenotype (SASP). The SASP can either promote or inhibit tumorigenesis as a function of the particular cellular context. Importantly, the mechanisms underlying SASP activation as well as its functional consequences are yet to be determined. Of note, OIS cells undergo a massive chromatin reorganization, with a re-localization of heterochromatin from the nuclear periphery to internal domains called senescence associated heterochromatin foci. The cause and consequences of this massive chromatin reorganization are largely unknown. I recently demonstrated that nuclear pore density increases in OIS and that this increase is required for heterochromatin reorganization. I further showed that depletion of the nuclear pore protein TPR in OIS cells impairs heterochromatin reorganization. Under these conditions, cell cycle arrest is maintained but the SASP is lost. Using a combination of microscopy and polymer in silico modelling, I will study how the nuclear pores can modulate the organization of chromatin and identify the domains and potential interactors of TPR involved in this function. I will then characterize how nuclear pores influence the activation of the SASP and explore the link between chromatin reorganization by nuclear pores and gene regulation. These studies should allow not only a better understanding of the senescent cell state but will also have the potential to open avenues with implications in the development of anti-cancer therapies.
On a longer term, my findings may as well be applicable to different cellular contexts, including early development.