葡萄糖对组蛋白H4 K8 2-羟异丁酰修饰的调控机制研究

近年来，许多与代谢密切相关的新型赖氨酸酰化修饰被发现，但这些修饰的功能和调控机制的研究明显滞后。组蛋白H4 K8位点的2-羟异丁酰修饰是一种在物种间保守的新型修饰，与基因的高转录活性相关。本课题组前期鉴定了其修饰酶与去修饰酶，同时发现葡萄糖可通过糖酵解途径影响该修饰在胞内的水平，但具体调控机制未知。我们提出糖代谢可能通过影响胞内修饰供体2-羟异丁酰辅酶A的水平或修饰酶复合物的2-羟异丁酰化酶活性来执行调控功能。本项目将利用代谢组和蛋白质组等分析方法，阐明培养基中糖浓度和类别与酵母体内2-羟异丁酰辅酶A含量的对应关系；利用生化、分子和遗传等技术，确定不同糖代谢产物对修饰酶复合物催化活性的作用，从而为验证上述假说提供实验证据，揭示糖酵解途径对H4 K8位点2-羟异丁酰化的调控机制。本项目的完成将建立该组蛋白修饰与核心代谢通路的关键链接，有助于解析该修饰在代谢类疾病中的潜在作用。

In recent years, many novel lysine acylation modifications closely related to metabolism have been identified, but the studies on the function and regulation of these modifications have lagged far behind. 2-hydroxyisobutyryl modification at the K8 site of histone H4 (H4K8hib) is one of the novel modifications conserved among species that is associated with the high transcriptional activity. We have identified its “writer” and “erasers” and found that glucose can affect the level of H4K8hib through glycolysis, but the detail mechanism remains unknown. We propose that glycolysis may regulate H4K8hib by affecting the level of intracellular donor 2- hydroxyisobutyryl-CoA or the enzyme activity of the “writer” complex. The metabolomic and proteomic analysis methods will be used to clarify the relationship between the concentration or type of sugar in the medium and the level of intracellular 2- hydroxyisobutyryl-CoA. The biochemical, molecular and genetic techniques will be used to determine the influence of the intermediate products in glucose metabolism on the catalytic activity of the “writer” complex. This project will reveal the regulatory mechanism of glycolysis pathway on 2-hydroxyisobutyrylation of H4 K8 and establish a key connection between this modification and core metabolic pathways, helping to elucidate the potential roles of this modification in metabolic diseases.