Tet1 Deficiency Leads to Premature Reproductive Aging by Reducing Spermatogonia Stem Cells and Germ Cell Differentiation

• Main Authors: Guian Huang, Linlin Liu, Huasong Wang, Mo Gou, Peng Gong, Chenglei Tian, Wei Deng, Jiao Yang, Tian-Tian Zhou, Guo-Liang Xu, Lin Liu
• Format: Article
• Language: English
• Published: Elsevier 2020-03-01
• Series: iScience
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220300924

Summary: Ten-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 that Tet1-deficient mice undergo a progressive reduction of spermatogonia stem cells and spermatogenesis and thus accelerated infertility with age. Tet1 deficiency decreases 5hmC levels in spermatogonia and downregulates a subset of genes important for cell cycle, germ cell differentiation, meiosis and reproduction, such as Ccna1 and Spo11, 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 of Tet2 deficiency 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. : Age; Male Reproductive Endocrinology; Cell Biology; Stem Cells Research Subject Areas: Age, Male Reproductive Endocrinology, Cell Biology, Stem Cells Research