基于多组学数据整合的衰老关键调节因子挖掘及其作用机制研究

深入解析衰老的调节机制对于延缓衰老和预防老年多发疾病具有重要意义。尽管以往研究鉴定了一些衰老相关基因，然而组织特异性衰老调节机制以及可用于临床转化的关键衰老调节因子还有待发掘。此外由于衰老是受多种因素调节的复杂过程，这大大增加了衰老研究的难度。针对这些问题，本项目拟用整合分析的方法，跨越五种小鼠组织（肝脏、心脏、骨骼肌、肾脏和大脑）比较衰老过程中表观遗传学修饰（DNA甲基化和三种组蛋白修饰）和基因表达（转录组和蛋白质组）的变化从而构建衰老的多维调节网络。通过将网络节点因子与人群衰老表型进行关联分析，挖掘调节衰老的关键因子。初步研究鉴定到ZIC1, CXXC1, ETS2, MECP2等转录因子并将继续对其作用机制开展研究，此外还发现并将揭示tRNA合成酶 (ARS) 和赖氨酸乙酰基转移酶 (KAT) 调节衰老的机制。综上，本研究有助于阐明衰老的多维调节机制并为人类抗衰老研究提供新的靶点。

A better understanding of the molecular mechanisms that regulate aging is invaluable for delaying the aging process and alleviation of aging-related diseases. Although a number of aging-related genes have been described, it is still to be discovered as for the tissue specific regulation of aging and key aging regulatory factors that are easily amenable for clinical translation into humans. To solve these issues, we plan to carry out an integrative analysis of epigenetic modifications including DNA methylation and 3 kinds of histone modifications, as well as changes of transcriptome and proteome, across 5 tissues including liver, heart, skeletal muscle, kidney, and brain from young and aged mice. We will explore regulatory footprints of aging to construct regulatory networks of aging across multiple molecular layers and extract promising aging regulators, which will be validated by association studies using aging-related traits from human populations. Preliminary studies have identified some key aging regulators including ZIC1, CXXC1, ETS2, MECP2 as candidates for further dissection of their roles in aging. Also, we discovered aminoacyl-tRNA synthetases (ARS) and lysine (K) acetyl transferases (KAT) as aging regulators and will further uncover the mechanisms. Taken together, results from this project will reveal regulatory mechanisms of aging at multiple molecular levels and provide novel anti-aging targets for clinical transformation.