衰老过程中CD8+T细胞三维基因组结构变化对转录调控的研究

免疫衰退是导致机体衰老的重要危险因素之一。通过前期研究，我们发现1）老年群体与年轻群体相比，其外周血CD8+T和Naive CD8+T细胞的数量显著减少；2）维持基因组三维结构的主要蛋白CTCF和RAD21，其染色质可及性区域及其基因表达量在人外周血单核细胞中均呈现出增龄性显著改变。这提示我们CD8+T在衰老过程中其三维基因组结构和细胞功能可能发生显著性改变。基于此，我们拟从人衰老过程中外周血CD8+T着手，从单分子三维基因组和表观遗传调控两个层面，借助最新的染色质构象捕获技术(ChIA-Drop)和单细胞染色质可及性方法，共同阐明：1.免疫衰退过程中染色质三维结构的变化特征；2.其结构变化是如何介导远程基因表达调控进而影响CD8+T衰老的发生。本项目有望通过研究染色质构象在免疫细胞衰老中的变化及异质性，发现调控免疫细胞衰老的新机制，为开发免疫衰退新标记物或靶点提供科学依据。

Immune decline is one of the most important risk factors for human aging. In our previous studies, we found that the number of CD8+T and Naive CD8+T lymphocytes in peripheral blood monocytes from the elderly group were significantly reduced compared with the young group. Besides, CTCF and RAD21, the major proteins that maintained the three-dimensional structure of the genome, whose chromatin accessibility region and gene expression level showed significant changes in PBMC cells during aging. These results suggested that the three-dimensional genome structure and cellular function of immune cell CD8+T might change significantly during the aging process. Based on this, we aimed to elucidate CD8+T in peripheral blood during human aging process from two levels of monomolecular three-dimensional genome and epigenetic regulation. Thus, by using the latest chromatin conformation capture technology (ChIA-Drop) and single-cell ATAC-seq (Assay for transposase-accessible chromatin) method, this project intended to jointly clarify two scientific questions: 1. The characteristics changes of the three-dimensional structure of chromatin during the process of immune decline; 2. How its 3D genomic structural changes mediated the regulation of remote gene expression and affected the occurrence of CD8+T senescence. This project was expected to study the changes and heterogeneity of chromatin structure in immune cell aging, to discover new mechanisms for regulating immune cell aging, and to provide scientific basis for the development of new markers or targets for immune decline.