Tet1 Deficiency Leads to Premature Reproductive Aging by Reducing Spermatogonia Stem Cells and Germ Cell Differentiation
Tet1 Deficiency Leads to Premature Reproductive Aging by Reducing Spermatogonia Stem Cells and Germ Cell Differentiation
复制标题
Tet1 缺乏通过减少精原干细胞和生殖细胞分化导致生殖早衰
DOI：
10.1016/j.isci.2020.100908
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发表时间：
2020-03-27
期刊：
影响因子：
5.8
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Huang, Guian;Liu, Linlin;Liu, Lin
10 - 11易位（泰特）酶参与DNA去甲基化，在调节胚胎发育、干细胞多能性和肿瘤发生中重要。DNA甲基化随年龄的变化已在各种体细胞类型中显示。我们研究Tet 1和Tet 2是否调节衰老。我们发现Tet 1缺陷小鼠精原干细胞和精子发生逐渐减少，从而加速了随着年龄的增长而不育。Tet 1缺乏会降低精原细胞中的5 hmC水平，并下调对细胞周期、生殖细胞分化、减数分裂和生殖重要的基因子集，如Ccna 1和Spo 11，导致过早的生殖衰老。此外，Tet 1和5 hmC都调节干细胞发育的关键信号通路，包括Wnt和PI 3 K-Akt，自噬和应激反应基因。与此相反，Tet 2缺乏对男性生殖衰老的影响较小。因此，Tet 1维持精原干细胞与年龄，揭示Tet 1在调节干细胞衰老的重要作用。
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.