生物大分子动态修饰是生命活动的重要调控机制。系统鉴定各种生物大分子修饰在体内的分布样式，研究其产生、消除、识别的分子机制，探讨其在生理病理条件下的动态调控规律有着重要的基础理论和实际应用意义。当前以赖氨酸甲基化/乙酰化/泛素化、精氨酸甲基化、酪氨酸/丝氨酸/苏氨酸磷酸化等为代表的蛋白质翻译后修饰已得到较为广泛而深入的研究。本项目拟针对目前尚未引起广泛关注的新型蛋白质修饰，比如组氨酸甲基化、丝氨酸乙酰化、赖氨酸羟基丁酰化等修饰展开深入研究，通过综合运用结构生物学、功能质谱学、化学生物学、细胞生物学、深度测序等现代技术手段完成上述新型甲基化、酰基化蛋白质修饰的修饰谱系统解析、生化分子机制阐明、以及病理调控机制分析等。相关工作的开展将揭示数种新型蛋白质甲基化和酰化修饰在生理或病理条件下的动态调控机制，并为相关疾病的诊断与治疗提供新思路。

Dynamic modification of biomacromolecules represents a key regulatory mechanism that controls diverse biological activities. Therefore, it is of great significance to profile the distribution pattern of biomacromolecular modifications, to reveal the molecular basis underlying their generation, removal and recognition, as well as to explore the dynamic regulation of biomacromolecular modifications under physiological or pathological conditions. Currently, protein post-translational modifications such as methylation/acetylation/ubiquitination of lysine, arginine methylation, phosphorylation of tyrosine/serine/threonine have been extensively studied. In this application, we aim to investigate several novel types of protein methyl/acyl modifications including histidine methylation, serine acetylation and lysine hydroxybutyrylation that are poorly explored. We shall apply our expertise in structural biology, functional mass spectrometry, chemical biology, cellular biology and deep sequencing to achieve systematic profiling, molecular and mechanistic characterization of the aforementioned protein methyl/acyl modifications in health and disease. We expect that the proposed studies will provide new mechanistic insights into the dynamic regulation of these novel protein methyl/acyl modifications, and pave the way for the diagnostic and therapeutical applications.