Défense de thèse en sciences biologiques

Roles of histone deacetylases (HDACs) in the senescent phenotype of skin cells

Jury

• GILLET Nicolas (UNamur), président
• CHAINIAUX Florence (UNamur), promotrice et secrétaire
• ABBADIE Corinne (Université de Lille, France)
• PEIXOTO Paul (Université de Bourgogne Franche-Comté, France)
• MOTTET Denis (ULiège)
• POUMAY Yves (UNamur)
  

Abstract

Ageing is characterized by a global slowdown of the physiological functions of the organism, predisposing to the appearance of age-related pathologies. Nine hallmarks of ageing have been described including cellular senescence. This latter is defined as an irreversible growth arrest related to the exhaustion of the proliferative capacities of the cells. Senescent cells accumulate with age in vivo and their presence has been shown to be associated with normal and pathological ageing. Senescent cells display several biomarkers, such as the expression of a particular secretome composed of cytokines, chemokines, growth factors and proteases and referred to as the senescence-associated secretory phenotype (SASP). SASP is mainly regulated at the transcriptomic level, and if several pathways have been highlighted to be associated to its regulation, some pathways are still to be discovered. It is in this context that we were interested in the impact of important regulators of the epigenetic regulation of gene expression, the canonical zinc-dependent histone deacetylases (HDACs), on the senescence of skin cells.

We first showed that the overall expression of HDACs was reduced during replicative senescence of dermal fibroblasts. This has been confirmed in epidermal keratinocytes. Treatment of fibroblasts and keratinocytes with SAHA (a pan-HDACs inhibitor also known as Vorinostat) induced the premature appearance of senescence in young cells, including the expression of several SASP factors. In order to identify if this effect was related to a specific HDAC, we invalidated HDAC2 and HDAC7 expression by using targeted siRNA in fibroblasts. Their invalidation led to a premature senescence phenotype, comparable to the one observed after the treatment of cells with SAHA. Interestingly, the re-expression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts allowed to extend their proliferative lifespan.

Overall, these results confirm that HDACs expression can modulate the senescent phenotype, reinforcing their pharmaceutical interest as therapeutic target in the context of healthy ageing.

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