Intergenic cis regulatory elements in the control of IL-2 and IL-21

项目摘要 自身免疫性疾病影响了2500多万美国人，造成了超过1000亿美元的经济影响 每年。这些疾病是由于限制T细胞的内在调节通路的破坏造成的 激活和分化，以及调节性T细胞(Treg)外源性抑制失败 常规T细胞(Tconv)的增殖和效应功能。人类和小鼠的遗传学研究 细胞因子IL-2与发生Grave‘s病、类风湿性关节炎、乳糜泻的风险密切相关 疾病、多发性硬化症、牛皮癣、克罗恩病、溃疡性结肠炎和1型糖尿病(T1D)。这个 大多数疾病相关的单核苷酸多态(SNP)位于~100kb或 白介素2和白介素21基因间的基因间隙以及白介素2之间遗传连锁的分子基础 而自身免疫力还不是很清楚。我们有新的证据表明，远端基因间的顺式调控元件 有助于调节IL-2。我们发现CD28共刺激诱导了远端元件之间的环路 和IL2启动子，而这个末端元件可以极大地增强启动子-报告基因中IL2的转录 化验。本申请中提出的研究将探索和建立远程监管 IL2基因座的结构，为重要的新的遗传学基础的理解铺平了道路 自身免疫性疾病。

Project Summary Autoimmune disease affects over 25 million Americans, and has an economic impact of over 100 billion dollars per year. These disorders result from a break down of the intrinsic regulatory pathways that limit T cell activation and differentiation, and from a failure of regulatory T cells (Treg) to extrinsically suppress conventional T cell (Tconv) proliferation and effector function. Genetic studies in both humans and mice strongly implicate the cytokine IL-2 in the risk of developing Grave's disease, rheumatoid arthritis, celiac disease, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and type 1 diabetes (T1D). The majority of the disease-associated single nucleotide polymorphisms (SNP) are located in the ~100 kb or intergenic space between the IL2 and IL21 genes, and the molecular basis for the genetic link between IL2 and autoimmunity is not understood. We have new evidence that distal, intergenic cis-regulatory elements contribute to the regulation of IL2. We find that CD28 costimulation induces looping between a distal element and the il2 promoter, and this distal element can greatly enhance IL2 transcription in promoter-reporter assays. The research proposed in this application will explore and establish the long-range regulatory architecture of the IL2 locus, paving the way for an important new understanding of the genetic basis for autoimmune disease.