新型蛋白质甲基化、酰基化修饰的系统鉴定及其动态调控机制研究

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.

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。

在本项目支持下，四年的研究工作取得了多项重要突破和重要研究进展，揭示了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，扩充了表观遗传调控元件库，揭示了表观调控因子在遗传信息解读、早期发育，以及癌症、白血病等人类疾病发生中的作用机理，有力促进了表观遗传学相关知识概念体系的发展和完善，而且为表观靶向的创新药物研发奠定了坚实基础，并为相关疾病的诊断与治疗提供新思路。截止2021年12月项目执行完毕（执行率100%）共发表33篇标注论文，其中包括3篇Nature、2篇Cell、1篇JACS、3篇Cell Res、4篇Cell Discov等。