H3K4甲基化转移酶Ash1l在免疫应答调控中的作用及机制研究

Histone modifying enzymes emerge as critical regulators of diverse biological and pathological processes and serve as potential diagnostic markers and intervention targets for human diseases. Regulatory T (Treg) cells are critical for maintenance of immune homeostasis and prevention of inflammatory diseases, but the function of histone modifying enzymes in the development of Treg cells and maintenance of immune tolerance remain poorly understood. We previously demonstrated Ash1l, a kind of H3K4 methyltransferase, is a crucial suppressor of TLR-induced innate immunity and prevents spontaneous autoimmune disorders, and is potentially involved in the generation of Treg cells via modulating TGF-β dependent Smad2/3 and Foxp3 expression. In this project, we aim to characterize the role of Ash1l in Treg cell-mediated immune tolerance and uncover the underlying epigenetic mechanisms. We will investigate the function of Ash1l in the generation, survival and immune suppressive function of TGF-β-mediated inducible Treg (iTreg) cells, the epigentic mechanism underlying Ash1l-mediated regulation of TGF-β dependent Smad/Foxp3 signaling in iTreg cells, and the development of T cell-mediated colitis and TNBS-induced colitis in Ash1l-deficient mice. Our research will add mechanistic insights into the role of histone modification in Treg cell generation and Foxp3 expression, clarify the epigenetic mechanisms in regulation of immune tolerance, and suggest possible new drug targets for intervention of inflammatory bowel diseases.

组蛋白修饰酶参与了众多生理病理过程，并可作为潜在的疾病诊断标识和干预靶点。调节性T细胞（Treg）是免疫系统实现负向调节及维持机体免疫稳态的关键环节，而对组蛋白修饰酶在Treg细胞分化发育及免疫耐受维持中的作用尚缺乏了解。我们的前期研究发现H3K4甲基化修饰酶Ash1l能显著抑制TLR触发的天然免疫应答及自身免疫性疾病发生，且参与Treg细胞体外分化并影响Smad2/3和Foxp3表达，本项目将在此基础上深入研究Ash1l调节Treg细胞分化及在免疫稳态维持中的功能和具体机制。主要研究内容包括1、Ash1l在Treg细胞分化、存活、活化中的作用；2、Ash1l调控TGFβ/Smad信号通路及Foxp3表达的分子机制；3、Ash1l在炎症性肠病发生发展中的作用及机制。本项目将揭示Treg细胞功能活化和免疫耐受的表观遗传学调控机制，为炎症性肠病的临床干预提供潜在靶点。

表观修饰分子参与了众多生理病理过程，并可作为潜在的疾病诊断标识和干预靶点。调节性T细胞（Treg）是免疫系统实现负向调节及维持机体免疫稳态的关键环节，而对表观修饰分子在Treg细胞分化发育及免疫应答调控中的作用尚缺乏了解。本项目发现H3K4甲基化转移酶Ash1L在调节性T细胞分化及自身免疫性疾病发生发展过程中发挥关键性调控作用。Ash1L可以促进iTreg细胞的生成，并保护小鼠抵御T细胞介导的结肠炎的发生发展。Ash1L依赖其SET结构域所介导的酶活性，通过直接靶向Smad2和Smad3的启动子区，活化Smad2/3转录表达。此外，本项目还发现了一条新的lncRNA lnc-Dpf3在树突状细胞迁移及其介导的炎症性疾病中发挥关键性调控作用。lnc-Dpf3负反馈抑制CCR7介导的转录因子HIF-1α活化及糖酵解基因LDHA表达，从而抑制DC的糖酵解水平，最终负向调控CCR7介导的DC迁移。.本项目阐明了表观修饰分子Ash1L分子和lnc-Dpf3分子在调控免疫应答和炎症性疾病中的重要作用并解释了其中的分子机制，从全新的角度展示了免疫稳态维持和炎症反应的表观遗传学调控机制，丰富了自身免疫性疾病和感染性疾病的分子机制，对于新型治疗方法的研发提供了新的思路与依据。