卵巢衰老的表观遗传特征及调控机制

Aging is closely related to telomere shortening. Emerging evidence demonstrates that DNA methylation and histone modifications known as epigenetic modifications alter during aging. The extent to which these changes are correlative versus cause effect is not yet clear and merits further exploration. This proposal will test the hypothesis that telomere, DNA methylation and repressive histone modifications play a complex, interactive role in maintaining and safeguarding stem cell potential during aging in ovary. We will determine the precise mechanism rather than observing correlative associations in reproductive age- related telomere function, DNA methylation, and heterochromatic histone modifications. Moreover, we will identify the most important genes and pathways for which altered patterns in methylation, telomere and heterochromatin contribute to age-related functional decline. We will use naturally reproductive aging mice, delaying aging mouse model, and Tet deficient mice showing accelerated reproductive aging to test the hypothesis and study the underlying mechanisms. Meanwhile we will use human materials donated by consent IVF patients from fertility center for comparative analysis and map epigenetic aging signatures of the ovary.

端粒缩短、DNA甲基化和组蛋白修饰异常与衰老关系密切。但其内在联系和发生机制仍不清楚。本研究在前期工作基础上，检验如下假设：即端粒、DNA甲基化和异染色质组蛋白修饰异常在细胞衰老中发挥复合交互作用。利用生殖自然衰老、延缓衰老以及过早衰老的Tet胞嘧啶羟甲基转移酶缺陷小鼠模型，通过全基因组分析结合重要基因功能解析，研究卵巢衰老相关的端粒、DNA甲基化和异染色质组蛋白修饰变化和相互关系，确定其精确调控机制。发掘与年龄增高相关的甲基化和异染色组蛋白修饰变化导致生殖细胞功能下降的关键基因和信号通路。同时利用人临床材料进行比较研究，阐明卵巢表观遗传衰老特征。

端粒缩短、DNA甲基化和组蛋白修饰异常与衰老关系密切。但其内在联系和发生机制任不清楚。本研究利用生殖自然衰老、延缓衰老、早衰的Tet胞嘧啶甲基转移酶缺陷小鼠模型，通过单细胞转录组测序和DNA甲基化测序明确：在自然衰老小鼠模型中参与蛋白质泛素化，肌动蛋白细胞骨架的基因被下调，而氧化应激信号通路被上调，同时端粒变短。然而白藜芦醇将自然衰老的卵母细胞的转录谱逆转到年轻的状态。在表观遗传水平上，白藜芦醇逆转了涉及微管和细胞骨架相关基因的甲基化修饰。然而，白藜芦醇对于延缓Tet2缺失引起的生殖早衰及表观遗传变化不明显。除了白藜芦醇可以延缓小鼠的自然衰老，我们还发现INK128可以通过抑制mTOR信号通路和免疫反应、提升线粒体功能，从而大大延长生殖干细胞移植后重建卵巢在衰老和早衰小鼠中的内分泌功能。最后利用人临床材料包括卵子和卵丘细胞通过转录组和端粒分析发现：端粒、转座元件以及如核糖体和溶酶体、代谢、DNA修复等重要成分和功能的变化参与女性的生殖衰老。总而言之，阐明卵巢衰老的表观遗传衰老特性、找寻延缓卵巢衰老的方法对于恢复卵巢表观遗传年轻状态是至关重要的，或许未来能够在临床上为卵巢早衰患者提供潜在的治疗方案。