Tet1 Deficiency Leads to Premature Reproductive Aging by Reducing Spermatogonia Stem Cells and Germ Cell Differentiation
Guian Huang,
Linlin Liu,
Huasong Wang,
Mo Gou,
Peng Gong,
Chenglei Tian,
Wei Deng,
Jiao Yang,
Tian-Tian Zhou,
Guo-Liang Xu,
Lin Liu
Affiliations
Guian Huang
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Linlin Liu
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Huasong Wang
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Mo Gou
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Peng Gong
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Chenglei Tian
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Wei Deng
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Jiao Yang
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China
Tian-Tian Zhou
State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China
Guo-Liang Xu
State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China; Corresponding author
Lin Liu
Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; Corresponding author
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
