树突状细胞亚群发育与功能的表观遗传学研究

Dendritic cells (DC), the most powerful antigen presenting cells linking the innate and adaptive immunity, play a central role in controlling the immune response and maintaining the immune tolerance. Epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence, including imprinting, gene silencing, X chromosome inactivation,regulation of histone modifications and heterochromatin, non-coding RNA etc. It has been shown that the epigenetic disorder is closely related to various human diseases, especially cancer or autoimmune diseases. Recently, the epigenetic regulation of the immune cells, particularly non-coding RNA (ncRNA) regulation, has become the forefront and hotspots in immunology research. At present however, there is very little knowledge on the functions of lncRNA in immune system and the function of miRNA in the differentiation and immune responses of conventional DCs. This project is therefore aiming to investigate the epigenetic regulation of differentiation and function of DC, particularly the function of ncRNAs on the differentiation and immune responses of different DC populations. The roles of these ncRNA in human diseases (e.g. SLE) will also been examined. This study should provide new insights into the molecular mechanisms for how the altered functions of ncRNA in DC differentitiaon and function may result in the development of autoimmune diseases and help to reveal the potential intervention targets for the treatment of these diseases.

树突状细胞（dendritic cell, DC）作为最强的专职抗原递呈细胞，处于诱导免疫应答和维持免疫耐受的中心环节。近年来具有不同功能特性的DC亚群被逐渐发现和鉴定出来。表观遗传是指基于非基因序列改变所导致的基因表达水平变化，在各种疾病特别是肿瘤和自身免疫性疾病中有重要作用。近来，对于免疫细胞的表观遗传调控，特别是非编码RNA的调控研究，成为了免疫学研究的前沿和热点。目前，国际上关于lncRNA在免疫细胞分化和应答中的功能尚未见报道，而miRNA在 DC亚群分化和应答中的功能也少有报道。因此，本项目将以DC为切入点，以miRNA和lncRNA对DC的分化和功能的调控为对象，深入研究DC分化应答的表观遗传调控，并结合疾病模型，全面阐述树突状细胞的表观调控在人类疾病（如：系统性红斑狼疮）中的作用，为相关疾病的治疗提供新的理论基础和干预靶点。

树突状细胞（dendritic cell, DC）作为最强的专职抗原递呈细胞，处于诱导免疫应答和维持免疫耐受的中心环节。近年来具有不同功能特性的DC亚群被鉴定出来。对这些DC亚群发育及功能的分子调控，特别是近年来对非编码RNA对DC发育及功能的调控研究成为免疫学研究的前沿和热点之一。 本项目以DC分化和功能为切入点，对非编码RNA的调控作用为研究重点，并结合疾病模型，深入分析阐明了数个miRNAs对DC分化及应答的表观遗传调控作用。我们的研究发现miR-223可通过靶向转录因子C/EBPb来抑制肠道DC及巨噬细胞分化及其介导的肠道炎症反应,在维持肠道稳态中起重要作用。我们还发现miR-21在浆细胞样DC(plasmacytoid DC, pDC)活化过程中表达显著上调，并通过调控PTEN进而正向调控I-型及III-型干扰素的产生，在抗病毒免疫反应中具有关键作用。此外，利用DC特异敲除动物模型，我们分析了miR17－92对DC功能的调控作用，初步发现 miR17－92可调控cDC1产生IL-12的能力进而影响T细胞的活化及效应性T细胞的分化。为进一步解析各类非编码RNA相互作用网络对DC发育及功能的调控作用，我们对各主要DC亚群进行了转录组学分析，对所获得数据的分析将有助于更确切的了解多种非编码RNA相互作用对DC亚群发育分化的重要调控作用。深入了解各种非编码RNA对DC发育及功能的调控作用，将为与DC发育与功能异常相关疾病的治疗提供新的理论基础和干预靶点。