Tet1/Tet2缺陷影响生殖衰老及其分子机制

Tet (ten-eleven translocation) 家族蛋白包括Tet1, Tet2 和Tet3，调控DNA去甲基化，在胚胎发育、干细胞多能性及肿瘤发生中起重要作用。端粒影响干细胞增殖和多能性维持、肿瘤发生以及衰老。Tet缺陷是否会导致早衰尚不清楚。我们发现Tet1/Tet2缺陷会导致端粒缩短，影响多能性干细胞分化发育能力，并且Tet1/Tet2缺陷小鼠随年龄增长表现出提早衰老症状。本项目试图研究Tets是否通过DNA去甲基化改变，使细胞端粒变短从而引起卵巢和睾丸早衰并揭示其分子机制。提出并验证四个方面的实验假设：1）Tet缺陷引起卵巢早衰；2）Tet缺陷加快雄性生殖能力随年龄增长而下降；3）Tet缺陷引起减数分裂异常、非整倍体增多及胚胎发育能力下降；4）Tet缺陷导致端粒变短和功能异常从而引起性腺早衰。期望为生殖衰老的机制探寻和医疗策略提供新思路，使人类生殖健康受益。

Tet (ten-eleven translocation) family proteins include Tet1, Tet2 and Tet3. Tets regulate DNA demethylation by epigenetic modification and play important roles in many biological processes, including embryonic development, stem cell pluripotency and differentiation, and tumorigenesis. Telomeres consist of repeated DNA repeats and associated proteins located at the end of chromosomes and maintain chromosomal stability. Telomere maintenance and function are involved in proliferation of pluripotent stem cells and pluripotency, tumorigenesis and aging including germ cells and ovarian aging. Recently we and others found that Tet1 and Tet2 deficiency leads to telomere shortening and reduced differentiation competency of pluripotent embryonic stem cells. Moreover, our preliminary observations indicate that Tet1 and Tet2 double knockout mice exhibit premature aging symptoms with age. This proposed study is to investigate whether Tets deficiency leads to gonad premature aging via telomere shortening of germ cells and somatic cells and the underlying molecular mechanisms using Tet1 and Tet2 double knockout mice. We propose the following four aims to be tested: 1) Tet1 and Tet2 deficient females exhibit premature ovarian aging; 2) Tet1 and Tet2 deficiency reduces fertility of males with age; 3) Tet1 and Tet2 deficiency impairs meiotic pairing and recombination, leading to aneuploidy and reduced embryo development; and 4) Tet1 and Tet2 mediated telomere shortening affect genome-wide gene expression which could be implicated in ovarian and testis dysfunction with age. We anticipate that the data obtained from this study will provide new mechanisms of reproductive aging and potential strategies for anti-gonad aging, benefitting human reproductive health.