卵巢衰老的表观遗传特征及调控机制

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。

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.