Ultra-Fast Epigenomic Maps for Monitoring Autoimmunity

用于监测自身免疫的超快速表观基因组图谱

• 批准号: 8732973
• 负责人: Howard Y Chang
• 金额: $ 14.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732973
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Lymphocytes; Basic Science; Bioinformatics; Biological; Biological Assay; Biological Markers; Cells; Chromatin; Clinical Research; Clinical Trials; Complex; Cyclosporine; Disease; Drug Controls; Epigenetic Process; Etiology; Gene Expression; Gene Expression Regulation; Genes; Genotype; Goals; Immune; Immune system; Immunosuppressive Agents; Inflammatory; Interleukin-1; Lymphocyte; Maps; Methods; Monitor; Patients; Regulatory Element; Research; Research Personnel; Role; STAT4 gene; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Site; Steroids; Systemic Lupus Erythematosus; Time; Tumor Necrosis Factor-alpha; Variant; XCL1 gene; epigenomics; genome-wide; human disease; inhibitor/antagonist; insight; monocyte; programs; response; tool; transcription factor

Altered gene regulation underlies many facets of autoimmunity and its treatments. Pathogenic autoantibodies and immune complexes ultimately exert their effects through cellular signal transduction to impact gene expression. The central roles of specific transcription factors in driving immune cell fates, and anti-inflammatory and immunosuppressive drugs that control gene expression - such as steroids, cyclosporine A (CsA), and inhibitors of JAKs, lnterieukin-1 (IL-1), Tumor Necrosis Factor (TNF), and B Cell Activating Factor (BAFF) - suggest the importance of understanding gene regulation in autoimmunity. Rather than simply observing changes in gene expression, recent epigenomic tools have made it possible to determine the causality of gene expression, revealing the specific transcription factors and regulatory elements driving different gene expression programs. However, existing experimental methods require 10 million cells or more per assay, and are complex and laborious to perform. These limitations have largely kept epigenomic analyses out of the reach of the clinical studies of human diseases, including autoimmunity. Here we propose to develop and apply a revolutionary new method called ATAC-Seq to map open chromatin sites genome-wide, to enable facile and rapid epigenomic studies of patients with autoimmune diseases and their response to treatments in real time. We will also explore the role of epigenetics in known genotypes of SLE patients with single nucleotide polymorphisms in genes such as Tyk2, STAT4, and IRF5. The end result will be a set of robust biomarkers and important biological insights into autoimmune and inflammatory diseases. The long term goal of our studies is to include ATAC-Seq in the ACE Shared Research Agenda, where it can be used by ACE investigators as part of their basic science projects, and as a mechanistic assay in ACE clinical trials.

基因调控的改变是自身免疫及其治疗的许多方面的基础。致病性 自身抗体和免疫复合物最终通过细胞信号转导发挥作用 影响基因表达。特定转录因子在驱动免疫细胞命运中的核心作用，以及 控制基因表达的抗炎和免疫抑制药物 - 例如类固醇， 环孢素 A (CsA) 以及 JAK、Interieukin-1 (IL-1)、肿瘤坏死因子 (TNF) 和 B 细胞抑制剂 激活因子 (BAFF) - 表明了解自身免疫中基因调控的重要性。相当 除了简单地观察基因表达的变化之外，最近的表观基因组工具使我们能够 确定基因表达的因果关系，揭示特定的转录因子和调控 驱动不同基因表达程序的元件。然而，现有的实验方法需要10 每次检测需要 100 万个细胞或更多，并且执行起来复杂且费力。这些限制在很大程度上 使表观基因组分析无法进行人类疾病（包括自身免疫性疾病）的临床研究。 在这里，我们建议开发并应用一种名为 ATAC-Seq 的革命性新方法来绘制开放染色质图谱 全基因组位点，以便能够对患有自身免疫性疾病的患者进行轻松快速的表观基因组研究 他们对治疗的实时反应。我们还将探讨表观遗传学在已知基因型中的作用 SLE患者存在Tyk2、STAT4、IRF5等基因单核苷酸多态性。最终结果 将是一组强大的生物标志物和对自身免疫和炎症的重要生物学见解 疾病。我们研究的长期目标是将 ATAC-Seq 纳入 ACE 共享研究议程， ACE 研究人员可以将其用作基础科学项目的一部分，并作为一种机制 ACE 临床试验中的测定。