Unraveling the requirement of SIRT7 in female and male reproduction

The union of an egg and sperm marks the beginning of life for sexually reproducing organisms. Successful fertilization will initiate the embryo development process, and its success relies on the quality of both gametes. To become developmentally competent, these gametes undergo multiple processes to ensure high quality and its maintenance. A major determinant of egg and sperm quality is genome integrity, which is key for generating healthy offspring. Sirtuins are a family of NAD+-dependent proteins that regulate cellular homeostasis, DNA repair and chromatin structure. Mammalian Sirtuin 7 (SIRT7) is widely recognized as a key regulator of genome stability through its roles in DNA damage repair and histone deacetylation, which influence chromatin compaction and gene expression. We aimed to determine whether SIRT7 plays a role in maintaining the quality of both eggs and sperm. Although previous studies described the function of SIRT7 in female meiosis, particularly during prophase I, its role in male gametogenesis was unexplored. Using whole-body SIRT7 knockout (KO) mice, we found that both males and females experience an accelerated loss of fertility. In both sexes, SIRT7 loss leads to hyperacetylation of histone H3 at lysine 36 (H3K36ac) in oocytes, spermatogonia, and spermatocytes. I show that this hyperacetylation alters chromatin accessibility, likely leaving germ cells more susceptible to genotoxic damage. Consistent with this model, SIRT7 depletion leads to DNA damage accumulation in oocytes and in spermatogonia. Like its role in oocytes, SIRT7 loss impairs Prophase I progression in spermatocytes, with the effect worsening with age in males. Taken together and based on our CUT&Tag analysis of H3K36ac in oocytes, our results establish SIRT7 as a critical factor in preserving genome integrity in both female and male germ cells through the deacetylation of H3K36ac.