抗原提呈细胞分化发育功能调控及参与炎症性自身免疫性疾病的表观遗传机制研究

Sets of epigenetic information such as DNA methylation, histone modification and non-coding RNA which constitute additional layers of transcription regulation have been discovered to play key roles in setting up and maintaining unique cell identity during eukaryotes development and differentiation. Epigenetic regulatory mechanisms are a central element in immune cell differentiation and function, allowing a specific gene expression pattern for lineage commitment and appropriate immune responses. From the point of view of epigenome, systematically analyzing genome-wide chromatin modifications provides powerful tools for data-based immunological research. Recently, more and more DNA methylomes and histone modifications in T and B cells have been widely revealed through microarray and deep sequencing combined with traditional epigenetic techniques such as bisulfite PCR and Chromatin IP (ChIP). But epigenetic regulation of antigen presenting cells including dendritic cells and macrophages are less reported. Through epigenomic techniques, we have obtained the profiles of DNA methylation, histone modification, transcriptome and miRNome during the differentiation and maturation of DCs and macrophages both in human and mice. In this project we intend to study the dynamic profiles of DNA methylation, histone modification, transcriptome and miRNome for DCs and macrophages, aiming to further discovery of epigenetic regulators in APC differentiation and maturation and reveal the significance of epigenetic regulators in the inflammatory autoimmune disease models. It will provide us with a way to mining key epigenetic regulator for identity and function of DCs, macrophages and outline new clues to study the pathogenesis of immunological disorders.

表观遗传修饰是以DNA甲基化、组蛋白修饰及非编码RNA为核心，在不同层次相互作用和整合，实现对基因转录和转录后调节。表观机制对免疫细胞分化发育和功能调节至关重要。树突状细胞、巨噬细胞作为专职性抗原提呈细胞APC在免疫应答与免疫病理中具有独特地位，但目前对其分化和功能调控表观机制尚不清晰。本课题组以表观组学体系，获得了人和小鼠树突状细胞、巨噬细胞不同分化成熟阶段的全基因组DNA甲基化谱、组蛋白修饰谱、表达谱及microRNA组的数据，拟在此基础上，深入寻找和分析调控APC分化成熟、功能特征和应答功能差异表观修饰位点，结合炎症性自身免疫性疾病等模型，系统研究表观调控因子在APC免疫识别和应答过程中的动态调控网络，揭示这些表观修饰位点在调控APC分化成熟及维持其特异性功能状态中的关键作用，探索免疫细胞功能调控和免疫识别与应答的新机制，提出免疫表观调控的新观点。

树突状细胞、巨噬细胞作为专职性抗原提呈细胞APC 在免疫应答与免疫病理中具有独特地位，但目前对其分化和功能调控尤其是表观调节机制仍不清晰。表观遗传修饰是以DNA 甲基化、组蛋白修饰及非编码RNA为核心，在不同层次相互作用和整合，实现对基因转录和转录后调节，表观调控机制对免疫细胞分化发育和功能调节发挥至关重要的作用。本课题组以表观组学体系，获得了人和小鼠树突状细胞、巨噬细胞不同分化成熟阶段的全基因组DNA 甲基化谱、组蛋白修饰谱、表达谱及microRNA 组的数据，在此前期基础上，我们在国家基金委本项目的资助下深入研究了树突状细胞和巨噬细胞分化、成熟、模式识别受体（TLR，RIG-I等）触发的天然应答功能过程中的精细调控机制，发现了一些新的表观调节分子和重要的蛋白翻译后修饰机制（泛素化修饰机制），阐明了这些调控机制在炎症性自身免疫性疾病中的作用和病理意义。本项目的研究结果鉴定了一些与表观调控相关的关键分子包括表观修饰酶和非编码RNA（Dnmt3a, FXBW7, TIPE2, Tet2, Rhbdd3, Ash1l, miR-223, miR-92a, miR-30b等）。发现Dnmt3a, FXBW7在调控I型干扰素产生和固有免疫应答中发挥正向调控作用，Siglec G负向调控RIG-I信号和I型干扰素；TIPE2, Tet2在炎症因子IL-6产生和消退中至关重要；Ash1l介导的表观修饰机制在关节炎发生发展中发挥关键作用，Ash1l在TLR介导天然免疫反应中的负向调控作用，Ash1l缺陷小鼠有明显自身免疫性疾病易感表型；miR-92a负向调控TLR信号触发的炎症因子IL-6和TNF，miR-223通过靶向Forkhead box protein O3促进RIG-I触发的I型干扰素产生，miR-30b促进调节性DC（DCreg）产生IL-10和NO，是一个负向的免疫调控因子。上述研究阐明了这些关键分子在调控炎症和自身免疫病中的生物学功能及其信号转导通路，并揭示了这些分子在疾病治疗中的潜在应用价值。上述研究结果已在Nat Immunol, Nat Commun, Cell, Immunity, JBC等主流期刊发表论文12篇。研究成果已在美国免疫学年会（AAI）、中德免疫学双边会议等国际会议进行了交流，培养了博士生8名和多名青年学者。