Epigenetic control of asthmatic inflammation by ATF3

ATF3 对哮喘炎症的表观遗传控制

• 批准号: 7589580
• 负责人: Mark Gilchrist
• 金额: $ 21.2万
• 依托单位: INSTITUTE FOR SYSTEMS BIOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589580
• 关键词: Alveolar Macrophages; Asthma; Binding; Binding Sites; Bioinformatics; Bronchial Spasm; Cells; Child; Chromatin; Chromatin Structure; Chromosomes, Human, Pair 11; Complex; DNA Binding; Data; Data Set; Development; Diagnosis; Disease; Elements; Environment; Epigenetic Process; Event; Extrinsic asthma; Fingerprint; Functional disorder; Gene Cluster; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Histone Acetylation; Histones; Human; Immune response; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knockout Mice; Lead; Link; Lung; Maps; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Ovalbumin; Pathogenesis; Pattern; Play; Prevention; Proteins; Public Health; Regulation; Research; Role; Scanning; Severity of illness; Source; Therapeutic Intervention; Wild Type Mouse; airway inflammation; beta-Chemokines; cell motility; chemokine; chromatin immunoprecipitation; clinically relevant; genome wide association study; genome-wide; genome-wide analysis; histone modification; macrophage; novel; novel diagnostics; overexpression; programs; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Sustained and coordinate gene transcription of the 12 CC chemokine gene clustered on chromosome 11 are necessary for inflammatory cell influx in asthma and controls disease severity. The long term goal of this R21 application is to investigate the mechanisms through which histone modifications (termed "epigenetic") modulate chemokine expression and airway inflammation. The disruption of histone modifications contribute to disease. I identified the transcription factor; ATF3, as a negative regulator of proinflammatory gene transcription via a histone modification mechanism. ATF3 plays a dominant role in the formation of specific chromatin structure, thereby controlling gene expression. Preliminary studies in a murine asthma model with ATF3-null mice show overwhelming inflammatory cell influx and overinduction of 8 CC chemokine genes in alveolar macrophages, providing strong evidence that ATF3 plays a critical role in asthma. To explore this further we will determine the asthmatic profiles of ATF3 and histone modifications in wild-type mice. We will then compare the profiles generated from ATF3-null mice to determine the epigenetic differences that lead to chemokine overinduction in the following specific aims. Aim1. Determine the CC chemokine expression profile in alveolar macrophages in asthma and determine the ATF3 DNA-binding profile within the CC chemokine cluster using chromatin-immunoprecipitation combined with promoter array (ChIP-to-chip). Aim2. Identify chromatin structure of this loci focusing on histone acetylation using ChIP-to-chip. Aim3. Determine novel transcriptional complexes involved in asthma using bioinformatic analyses. This study will define the histone profile that leads to overexpression of CC chemokines in asthma, and delineate the histone-modifying role of ATF3. In addition, genome-wide analysis of this dataset will reveal further genes whose expression is modulated by histone modification events and the extent of these changes leading to the progression of allergic asthma. The data can be used to define epigenetic "fingerprints" of asthma for further study in humans. We anticipate that this will lead to a better understanding of the role of histone modifications in asthma pathogenesis, and ultimately better strategies for diagnosis, treatment and prevention. PUBLIC HEALTH RELEVANCE: Allergic asthma is a major public health problem, and the morbidity and motility of asthma have increased significantly in the last two decades, particularly in children. Data generated from this proposal will define novel mechanisms that control the inflammation that is linked to disease severity. This information can lead to the discovery and development of novel diagnostic markers as well as new targets for therapeutic intervention in this disease.

描述（由申请人提供）：11号染色体上簇集的12 CC趋化因子基因的持续和协调基因转录对于哮喘中的炎性细胞流入和控制疾病严重程度是必需的。这项R21应用的长期目标是研究组蛋白修饰（称为“表观遗传”）调节趋化因子表达和气道炎症的机制。组蛋白修饰的破坏有助于疾病。我确定了转录因子; ATF 3，作为通过组蛋白修饰机制的促炎基因转录的负调节因子。ATF 3在特定染色质结构的形成中起主导作用，从而控制基因表达。在小鼠哮喘模型与ATF 3-null小鼠的初步研究显示压倒性的炎性细胞流入和过度诱导的8 CC趋化因子基因在肺泡巨噬细胞，提供了有力的证据表明，ATF 3在哮喘中起着关键作用。为了进一步探索这一点，我们将确定野生型小鼠中ATF 3和组蛋白修饰的哮喘特征。然后，我们将比较从ATF 3缺失小鼠产生的谱，以确定导致趋化因子过度诱导的表观遗传差异，具体目标如下。目标1.测定哮喘患者肺泡巨噬细胞中CC趋化因子的表达谱，并使用染色质免疫沉淀结合启动子阵列（ChIP-to-chip）测定CC趋化因子簇中的ATF 3 DNA结合谱。目标2。使用ChIP-to-chip鉴定该基因座的染色质结构，重点是组蛋白乙酰化。目标3。使用生物信息学分析确定哮喘中涉及的新转录复合物。本研究将明确导致哮喘中CC趋化因子过度表达的组蛋白谱，并描述ATF 3的组蛋白修饰作用。此外，对该数据集的全基因组分析将揭示其表达受组蛋白修饰事件调节的其他基因以及导致过敏性哮喘进展的这些变化的程度。这些数据可以用来定义哮喘的表观遗传“指纹”，以供进一步的人类研究。我们预计这将导致更好地了解组蛋白修饰在哮喘发病机制中的作用，并最终制定更好的诊断、治疗和预防策略。公共卫生关系：过敏性哮喘是一个主要的公共卫生问题，在过去的二十年中，哮喘的发病率和运动性显著增加，特别是在儿童中。该提案产生的数据将定义控制与疾病严重程度相关的炎症的新机制。这些信息可以导致发现和开发新的诊断标志物以及用于这种疾病的治疗干预的新靶点。