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

描述(申请人提供)：自身免疫性疾病影响超过2500万美国人，每年造成超过1000亿美元的经济影响。这些疾病是由于限制T细胞活化和分化的内在调节通路的崩溃，以及调节性T细胞(Treg)未能从外部抑制常规T细胞(Tconv)的增殖和效应器功能。在人类和小鼠中进行的遗传学研究强烈表明，细胞因子IL-2与发生格雷夫氏病、类风湿性关节炎、乳糜泻、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)的风险有关。大多数疾病相关单核苷酸多态(SNP)位于IL2和IL21基因之间的~100kb或基因间隙，IL2与自身免疫之间遗传联系的分子基础尚不清楚。我们有新的证据表明，远端、基因间的顺式调控元件参与了IL2的调控。我们发现CD28共刺激诱导了远端元件和IL2启动子之间的环路，并且在启动子-报告分析中，这个远端元件可以极大地增强IL2的转录。本申请中提出的研究将探索和建立IL2基因座的远程调控架构，为重新认识自身免疫性疾病的遗传基础铺平道路。

DESCRIPTION (provided by applicant): Autoimmune disease affects over 25 million Americans, and has an economic impact of over 100 billion dollars per year. These disorders result from a breakdown 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.