摘要：SummaryTen-eleven translocation (Tet) enzymes are involved in DNA demethylation, important in regulating embryo development, stem cell pluripotency and tumorigenesis. Alterations of DNA methylation with age have been shown in various somatic cell types. We investigated whether Tet1 and Tet2 regulate aging. We showed thatTet1-deficient mice undergo a progressive reduction of spermatogonia stem cells and spermatogenesis and thus accelerated infertility with age.Tet1deficiency decreases 5hmC levels in spermatogonia and downregulates a subset of genes important for cell cycle, germ cell differentiation, meiosis and reproduction, such asCcna1andSpo11, resulting in premature reproductive aging. Moreover, Tet1 and 5hmC both regulate signaling pathways key for stem cell development, including Wnt and PI3K-Akt, autophagy and stress response genes. In contrast, effect ofTet2deficiency on male reproductive aging is minor. Hence, Tet1 maintains spermatogonia stem cells with age, revealing an important role of Tet1 in regulating stem cell aging.Graphical AbstractDisplay OmittedHighlights•Tet1 regulates stem cell aging and differentiation•Tet1 plays an important role in maintaining spermatogonial stem cells•Loss of Tet1 results in exhaustion of spermatogonia and premature reproductive aging•Effect of Tet2 deficiency on reproductive aging in males is minorAge; Male Reproductive Endocrinology; Cell Biology; Stem Cells Research
