端粒染色质结构在细胞衰老中的作用研究

端粒是真核生物染色体末端的特殊结构，由端粒DNA及端粒结合蛋白组成。经典端粒衰老学说认为正常体细胞的端粒长度随着细胞分裂逐渐缩短，当短到一定程度会激活DNA损伤信号，进而诱导细胞衰老。然而，许多研究表明端粒长度并不是复制性衰老的唯一因素。.端粒染色质结构包括端粒DNA结构以及异染色质特征。前期工作中，我们发现正常体细胞进入衰老阶段，端粒长度缩短并不显著，但端粒T-Loop结构以及端粒结合蛋白表达量均明显下降。这些结果提示端粒染色质结构在细胞衰老过程中起到重要作用，但作用机制还需进一步阐明。.基于此，本课题将综合利用生化、细胞以及超分辨技术研究：(1)细胞衰老过程中端粒染色质结构变化；(2)端粒长度、表观遗传修饰、端粒结合蛋白在端粒染色质结构变化中的作用；(3)端粒染色质结构改变是如何激活DNA损伤信号进而诱导细胞衰老。进而阐明端粒染色质结构在细胞衰老过程中的重要功能，扩充经典端粒衰老学说。

Telomeres are specialized DNA-protein complexes at the ends of linear chromosomes that prevent fusion of chromosomes ends, and inhibit enzyme-mediated degradation and illegitimate recombination of chromosomal DNA. In normal somatic cells, telomeres shorten progressively per replicative cycle. Once telomeres regress to a critical length, the short telomere trigger a state known as ‘telomere crisis’, followed by replicative senescence. However, evidences have shown that telomere length is not the only restraint to replication-induced cell senescence..Telomere DNA structure and heterochromatin characteristics constitute telomere chromatin structure. Our new data show that telomeres length do not regress remarkably, but telomere T-Loop structure and the transcription of shelterin complex proteins decrease dramatically when cells enter into senescence, indicating that telomere chromatin structure plays an important role in cell senescence. .This project will comprehensively utilize advanced technology methods to study chromatin structure transformation during cell senescence, to investigate the function of telomere length, epigenetic modification and shelterin complex on chromatin structure transformation, and how the chromatin structure transformation activates DNA damage signal to induce cell senescence. Finally, we will determine the effect of telomere chromatin structure on cell senescence, and expand classic telomere theory of aging.