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A role for nuclear pore complexes in chromatin organization during early development?

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

Cancerous cells proliferate in an uncontrolled manner. However some of these cells are arrested and can not divide anymore. This is called cellular senescence. Senescent cells secrete molecules that can, on one hand reinforce senescence, but on the other hand promote tumour formation – so senescence is considered as a double-edged sword from the persepective of cancer. The genome of senescent cells is organized differently from non senescent cells. The role of this genome reorganization is unclear and we do not know whether it is necessary to arrest cell division. I showed that increase in nuclear pores density is responsible for genome reorganization in senescent cells and explored its role. My results demonstrate that perturbing genome reorganization in senescent cells can maintain cellular arrest but abolishes the secretion of molecules typical of senescent cells, therefore only preserving the anticancerous effect of senescence.
DNA is the support of genetic information. The association of proteins with DNA allows its organization into chromatin which is stored in cells nuclei. The chromatin can be more or less compacted and this compaction state correlates with the activation of genes. The compacted form of chromatin, the heterochromatin is usually inactive whereas the open form of chromatin contains more active genes. Therefore the regulation of chromatin compaction is key for the regulation of gene expression.
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.
Our results impact different fields of study. These include senescence (oncogene induced senescence, OIS), but also the roles of nuclear pores besides nuclear transport and the impact of chromatin organisation on gene expression. My data show that the deletion of translocated promoted region (TPR) reverses the formation of senescence associated heterochromatin foci (SAHF) while maintaining cell cycle arrest. In contrast to this, SASP gene expression is abolished. This is the first evidence that cell cycle arrest (anti tumorigenic) can be uncoupled from SASP (pro-tumorigenic) in OIS. My project allows further understanding of the mechanisms leading to this uncoupling. It could therefore be the basis to the development of new therapeutic approaches, that could prevent cancers by targeting nuclear pores.
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.
Model showing repulsion of heterochromatin at nuclear pores