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

控制 IL-2 和 IL-21 的基因间顺式调控元件

• 批准号: 8776923
• 负责人: ANDREW D WELLS
• 金额: $ 21万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776923
• 关键词: Abscisic Acid; Affect; American; Architecture; Autoimmune Diseases; Autoimmunity; Binding; Biological Assay; Boundary Elements; Bypass; CD28 gene; CD4 Positive T Lymphocytes; Celiac Disease; Cell Death; Cells; Chromatin; Chromosomes; Crohn' s disease; Development; Disease; Disease susceptibility; Distal; Elements; Engineering; Enhancers; Epigenetic Process; Equilibrium; Failure; Formaldehyde; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Genome; Growth Factor; Health; Histones; Homeostasis; Hormones; Human; Human Genetics; IL2 gene; Immune; Immune Tolerance; Immune system; Immunity; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Junk DNA; Ligation; Link; Luciferases; Molecular; Multiple Sclerosis; Mus; Natural Killer Cells; Pathway interactions; Plants; Process; Psoriasis; Recombinants; Regulation; Regulatory Element; Regulatory Pathway; Regulatory T-Lymphocyte; Reporter; Research; Retroviral Vector; Rheumatoid Arthritis; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Site; Stimulus; Surveys; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Transcription Coactivator; Ulcerative Colitis; Untranslated RNA; Work; base; chromatin remodeling; cytokine; economic impact; genome wide association study; interleukin-21; novel; promoter; response; small molecule

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.

描述（由申请人提供）：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细胞激活和分化的内在调节途径的破坏，以及调节性T细胞（Treg）外部抑制常规T细胞（Tconv）增殖和效应功能的失败造成的。人类和小鼠的遗传学研究强烈暗示细胞因子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。大多数疾病相关的单核苷酸多态性（SNP）位于IL2和IL21基因之间的约100 kb或基因间空间，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，基因间顺式调控元件有助于il - 2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，并且该远端元件可以在启动子报告子分析中大大增强il2转录。本申请提出的研究将探索和建立IL2位点的远程调控结构，为对自身免疫性疾病的遗传基础的重要新认识铺平道路。