Deciphering epigenetic mechanisms of genome maintenance during natural and premature reproductive aging

Animal aging is tightly linked to chromatin regulation and genome integrity. While epigenetic aging has been extensively characterized in somatic tissues, the relationship between chromatin changes and the aging of reproductive cells remains largely unexplored. The Sir2 family of proteins or Sirtuins play pivotal roles in animal longevity by promoting cellular stress responses involving metabolic and epigenetic regulation. Recently, mammalian Sirtuins have gained much attention for their functions in reproductive processes including germ cell development and meiotic maturation. Sirtuins are expressed at variable levels in reproductive tissues, being SIRT7 among the most highly expressed in early germ cells. Our results indicate that SIRT7 controls H3K36ac deposition in germ cells and its deficiency accelerates reproductive aging in mice. How H3K36ac contributes to reproductive senescence is still not understood. Notably, emerging evidence indicates that Sirtuin activity may protect the gonads from the toxic effects of chemotherapy, underscoring their importance to sustain reproductive capabilities under different health conditions. Using the strengths of mouse genetics, CRISPR/Cas9 approaches, state-of-the-art genomics and cutting-edge gonadal tissue culture, this project will characterize novel epigenetic mechanisms associated with Sirtuin activity and their impact on the aging of reproductive cells.