组蛋白H2A泛素化修饰作为高度保守衰老标志物的鉴定和机制研究

The long-lived proteome constitutes a pool of exceptionally stable proteins with limited turnover. The contribution of long-lived proteome to lifespan is not well-understood. Previous studies on ubiquitin-mediated protein degradation primarily focused on short-lived proteins; how ubiquitylation modifies the long-lived proteome and its regulatory effect on adult lifespan is unclear. Here we profiled the age-dependent dynamics of long-lived proteomes in Drosophila by mass spectrometry using stable isotope switching coupled with antibody-enriched ubiquitylome analysis. Our data describes the first atlas of long-lived proteins in somatic and reproductive tissues of Drosophila during adult lifespan, and reveals a preferential ubiquitylation of older proteins in aging. We identify an age-modulated increase of ubiquitylation on long-lived histone 2A protein (ubH2A) in Drosophila, which is evolutionarily conserved in mouse and human. Moreover, a reduction of ubH2A in mutant flies is associated with extended lifespan and enhanced ability to handle oxidative stress. In the present study, we propose to explore the epigenetic landscape of ubH2A using human cells and mouse tissues, and further connect changes in ubH2A profile with gene expression. Together, we aim to reveal a new conserved hallmark of aging that links epigenetic modulation on the long-lived histone protein to adult lifespan, providing novel conceptual insight and potent therapeutic targets for aging and age-related diseases, and fulfilling the aim and scope of the Major Research Plan of the National Natural Science Foundation of China.

衰老是随年龄增加，机体表现出生理机能渐进性下行，并伴随疾病发生及个体死亡率的显著上升。申请人前期工作发现组蛋白H2A不仅是一类新的长寿蛋白，而且组蛋白H2A的单泛素化修饰在果蝇、小鼠全脑及人大脑中均随年龄显著上调。本项目以组蛋白H2A泛素化修饰为研究对象，系统鉴定组蛋白泛素化作为衰老标志物的变化过程和规律；分别以人IMR90细胞、小鼠器官和果蝇为模型，构建组蛋白泛素化精细表观谱图，揭示表观修饰变化与基因转录表达在衰老进程中的动态调控关系。本项目的实施将阐明衰老及衰老向退行演化的新型生物标志物及分子机制，为衰老与退行相关疾病治疗提供线索和靶点，与指南目标高度吻合。

衰老是随年龄增加，机体表现出生理机能渐进性下行，并伴随疾病发生及个体死亡率 的显著上升。本项目发现组蛋白H2A不仅是一类新的长寿蛋白，而且组蛋白H2A的 单泛素化修饰在果蝇、小鼠全脑及人大脑中均随年龄显著上调。本项目以组蛋白H2A泛素 化修饰为研究对象，系统鉴定组蛋白泛素化作为衰老标志物的变化过程和规律;分别以人 IMR90细胞、小鼠器官和果蝇为模型，构建组蛋白泛素化精细表观谱图，揭示表观修饰变 化与基因转录表达在衰老进程中的动态调控关系。ubH2A在不同物种中的共性和差异化修饰，并一步结合多组学研究手段，发现潜在的分子效应及对下游信号通路的影响。作为器官衰老重大研究计划培养项目，本研究具有开拓性指导意义。 该工作以研究文章（Research Article）的形式发表在《自然-通讯》杂志（Nature Communications）。负责人为通讯作者。项目批准号（91849109）为第一标准。文章发表后被同行推荐至F1000（recommendation，rated** very good）。