组蛋白β-羟丁酰基化修饰的识别与调控机制研究

β-hydroxybutyrylation (bhb) of histone is the marker of gene activation, which is suggested to be an important way for eukaryotes to deal with metabolic stress like starvation. In addition, histone β-hydroxybutyrylation might be involved in epilepsy treatment and have protective roles in some neurodegenerative diseases. However, little is known about the dynamics and recognition of histone β-hydroxybutyrylation and its function. Investigation the regulation and recognition mechanism of histone β-hydroxybutyrylation will promote our understanding of its role in gene activation upon environmental signals and therapy for neurodegenerative diseases such as epilepsy. The novel chemical biological technique CLASPI will be applied to identify new writers, erasers and readers of histone β-hydroxybutyrylation in this study and their physiological roles will be explored. Both chemical and biological methods are used in this study. By completing this project, we will identify 3-5 new writers, erasers or readers of histone β-hydroxybutyrylation, and elucidate the mechanism for regulation and recognition of histone β-hydroxybutyrylation. We will illuminate the function of histone β-hydroxybutyrylation under physiological and pathological conditions, and publish 3-5 papers in high profile SCI journals.

组蛋白β-羟丁基化修饰（β-hydroxybutyrylation，bhb）参与基因转录激活调控，在个体对营养摄入状态变化的响应中起着重要作用，并且可能与癫痫等神经性疾病的预防和治疗密切相关。但是，目前对组蛋白β-羟丁基化修饰的动态调控和识别机制及其生理功能知之甚少。对组蛋白β-羟丁基化修饰调控与识别的研究，有助于理解其响应外界信号调控基因转录的分子机理，以及在神经性疾病（如癫痫）治疗中的作用机理。本项目将应用和优化CLASPI这一创新化学生物学方法，鉴定组蛋白β-羟丁基化修饰的修饰酶、去修饰酶和识别蛋白，并研究其在细胞生命活动中的作用。本项目的研究在方法学上体现了化学与生物学交叉的特色，将鉴定3-5个新的组蛋白β-羟丁基化修饰的修饰酶、去修饰酶或者识别蛋白，揭示该修饰的动态调控与识别的分子机理，阐明其在生理和病理条件下的作用机制，发表3-5篇高水平SCI论文。

组蛋白修饰受修饰酶（writers）和去修饰酶（erasers）的动态调控，还可以作为一种表观遗传密码由识别蛋白（readers）识别从而启动下游一系列生物学效应。组蛋白β-羟丁基化修饰参与基因转录激活调控，可能与癫痫等神经性疾病相关；组蛋白乳酰化修饰可以通过激活特定基因的转录促进巨噬细胞的极化；组蛋白5-羟色胺修饰则参与神经元细胞的分化。目前对这三种新型组蛋白修饰的动态调控和识别机制及其生理功能仍知之甚少。在本项目资助期间，我们应用和优化CLASPI这一创新化学生物学方法，鉴定了组蛋白β-羟丁基化修饰的去修饰酶Sirt2和HDAC1以及识别蛋白Yeats2，组蛋白乳酰化修饰的去修饰酶Sirt1、2、3、5和HDAC3，组蛋白5-羟色胺修饰的特异识别蛋白WDR5。通过体外生化实验和细胞内功能实验，阐释了Sirt2下调组蛋白乳酰化修饰调控基因转录的分子机制，以及WDR5特异识别组蛋白5-羟色胺修饰促进神经母细胞瘤细胞增殖的分子机制。项目资助期间，我们与多个实验室开展合作研究，发表标注资助号的SCI 论文2 篇，培养1名硕士获得硕士学位，3名博士获得博士学位。如上所述，我们按照计划，圆满地完成了相应的研究任务。