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超过2500万美国人，经济影响超过1000亿美元 每一年。这些疾病是由于限制T细胞增殖的内在调节途径的破坏而引起的。 活化和分化，以及调节性T细胞（Treg）无法外抑制 常规T细胞（Tconv）增殖和效应子功能。人类和小鼠的基因研究 强烈暗示细胞因子IL-2在发生格雷夫斯病，类风湿性关节炎，乳糜泻， 疾病、多发性硬化、牛皮癣、克罗恩病、溃疡性结肠炎和1型糖尿病（T1 D）。的 大多数疾病相关的单核苷酸多态性（SNP）位于~100 kb或 IL 2和IL 21基因之间的基因间隔，以及IL 2和IL 21之间遗传联系的分子基础 自身免疫性还不清楚我们有新的证据表明远端基因间顺式调控元件 有助于调节IL 2。我们发现，CD 28共刺激诱导远端元件之间的循环， 和IL 2启动子，并且该远端元件可以极大地增强IL 2在启动子-报告基因中的转录。 测定。本申请中提出的研究将探索和建立远程调控机制， IL 2基因座的结构，为对IL 2基因座的遗传基础的重要新理解铺平了道路。 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.