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Décryptage des processus transcriptionel dans la sénescence cellulaire : le rôle de PARP1 dans la Régulation de l'expression génique associée à la sénescence

Abstract : Cellular senescence is a complex stress response that arrests cell proliferation and is accompanied by widespread changes in metabolism, chromatin structure, and gene-expression, including the overexpression and secretion of inflammatory factors. Cellular senescence is health-promoting as a tumor-suppressive mechanism, facilitating embryonic development and tissue regeneration. However, it is also considered a major contributor to aging and age-related diseases, mostly through its inflammatory phenotype, the so-called SASP (senescence-associated secretory phenotype). Current research supports the role of PARP1 (Poly (ADP-ribose) polymerase 1) in the transcriptional regulation of inflammatory processes and modulation chromatin structure. However, the exact mechanisms by which PARP1 exerts its regulatory functions, and its roles in the context of regulating senescence gene-expression are underexplored.In my thesis, I set out to define the functional role of PARP1 catalytic and chromatin binding activities in gene regulation and chromatin structure in cells undergoing senescence. I performed time-resolved transcriptomics, chromatin-accessibility studies, and mapping of the genome-wide locations of PARP1 using ChIP-seq and ADP-ribosylated chromatin using a novel technique CRAP-seq (Chromatin-Ribosylation-Affinity-Pulldown).Together, I identified a dichotomy of PARP1 function – one related to its enzymatic ADP-ribosylation activity and the other related to its non-enzymatic chromatin binding activity – with distinct impacts on the senescence transcriptional program. Based on these findings, I can define a novel and global role for PARP1 in and chromatin structure modulation by stabilizing nucleosomes positioning at gene promoters and ADP-ribosylation of cis-regulatory modules to fine-tune transcription of lowly expressed genes. Indeed, based on my investigations, the role of PARP-inhibitors in senescence targeting therapies (senolytic therapies) for the treatment of age-related pathologies can be envisioned.
Keywords : Aging Cancer Senescence
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Theses
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Lucas Robinson. Décryptage des processus transcriptionel dans la sénescence cellulaire : le rôle de PARP1 dans la Régulation de l'expression génique associée à la sénescence. Médecine humaine et pathologie. Université de Paris, 2019. Français. ⟨NNT : 2019UNIP7099⟩. ⟨tel-03145221⟩

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