Bromodomain-containing Protein 4 in Profibrotic Gene Expression and Lung Fibrosis

含溴结构域蛋白 4 在促纤维化基因表达和肺纤维化中的作用

• 批准号: 10556325
• 负责人: Yan Sanders
• 金额: $ 51.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-03-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556325
• 关键词: ATAC-seq; Acetylation; Acetyltransferase; Actins; Adult; Affect; Apoptosis; Automobile Driving; Binding; Binding Sites; Biological Assay; Bromodomain; C57BL/6 Mouse; CRISPR/Cas technology; Cardiac; Cell physiology; Cells; Cellular Stress; Chromatin; Collagen; Data; Disease; Down-Regulation; EP300 gene; Elements; Enhancers; Enzymes; Epigenetic Process; Etiology; Family; Fibroblasts; Fibrosis; Gene Expression; Genes; Genetic Transcription; Hematology; Histone Acetylation; Histones; Kidney; Knockout Mice; Liver Fibrosis; Lung; Lung diseases; Lysine; Maps; Mediating; Methods; Mus; Myofibroblast; NADPH Oxidase; Organ; Pancreas; Pathogenesis; Phase I/II Clinical Trial; Phenotype; Play; Post-Translational Protein Processing; Pre-Clinical Model; Process; Promoter Regions; Proteins; Pulmonary Fibrosis; Reader; Regulatory Element; Reporting; Research; Resolution; Role; Small Interfering RNA; Smooth Muscle; Solid Neoplasm; Testing; Therapeutic; Transcriptional Regulation; Transforming Growth Factors; Transposase; Up-Regulation; aged; cell type; chromatin immunoprecipitation; chromatin modification; efficacy evaluation; epigenetic regulation; epigenomics; genome-wide; histone acetyltransferase; histone modification; idiopathic pulmonary fibrosis; improved; in vivo; in vivo Model; inhibitor; lung injury; lung repair; member; molecular targeted therapies; mortality; novel; novel therapeutics; pharmacologic; profibrotic cytokine; promoter; recruit; repaired; response; therapeutic target; transcription factor; transcriptional reprogramming

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder of unknown etiology. IPF is characterized by altered epigenetic state. Epigenetic alterations are potentially reversible, thus are attractive therapeutic targets. Chromatin structural remodeling through histone post- translational-modifications control transcriptional responses. Acetylated histone marks as well as some transcriptional factors are recognized by bromodomains (readers). Bromodomain- containing protein (Brd) 4 is a member of the bromodomain and extraterminal (BET) family, which binds to cell type-specific enhancers and promoters. Brd4 has been reported to be essential for enhancer-mediated pro-fibrotic genes expression in many organ fibrosis. However mechanisms of how Brd4 regulates genome-wide pro-fibrotic responses and its interaction with other his acetyltransferase, such as p300, is not clear. Fibrotic responses involve many cellular processes, including epigenetic alterations. Our preliminary data show that by blocking Brd4, multiple profibrotic genes can be downregulated; inhibition of Brd4 can disrupt the association of p300 and H3K27ac with profibrotic genes promoter region. We hypothesis that Brd4 affects chromatin accessibility, mediates the up-regulation of profibrotic genes through interaction with p300 by acetylating active enhancer mark H3K27ac during lung injury and repair process. Our aims are: 1. Determine the effects of Brd4 inhibition on profibrotic responses in lung fibroblasts; 2. Determine if Brd4 through p300 mediates histone acetylation to regulate profibrotic genes expression, 3. Determine the in vivo targeting of Brd4 inhibition in pre-clinical models of lung fibrosis. Results from this research will make a significant impact on our understanding of the role of Brd4 in epigenetic regulation in the pathobiology of IPF.

项目总结 特发性肺纤维化(IPF)是一种病因不明的致命性肺部疾病。IPF是 以表观遗传状态改变为特征的。表观遗传改变可能是可逆的，因此 都是有吸引力的治疗靶点。组蛋白后的染色质结构重塑 翻译修饰控制转录反应。乙酰化组蛋白标记以及 一些转录因子被溴域(读者)识别。溴域- 包含蛋白(Brd)4是溴域和端外蛋白(BET)家族的成员，它 与特定细胞类型的增强子和启动子结合。据报道，BRD4对 增强子介导的促纤维化基因在许多器官纤维化中的表达。然而，机制 Brd4如何调控全基因组促纤维化反应及其与其他组氨酸的相互作用 乙酰转移酶，如p300，目前还不清楚。纤维化反应涉及许多细胞过程， 包括表观遗传改变。我们的初步数据显示，通过阻止Brd4，多个 促纤维化基因可以下调；抑制Brd4可以破坏p300和p300之间的关联。 H3K27ac带有促纤维化基因启动子区域。我们假设Brd4影响染色质 可及性，通过与p300的相互作用介导促纤维化基因的上调 乙酰化活性增强子标记H3K27ac在肺损伤修复过程中的作用我们的目标是： 1.检测Brd4抑制对肺成纤维细胞促纤维化反应的影响； 确定Brd4至p300是否介导组蛋白乙酰化以调节促纤维化基因 表达，3.在临床前肺模型中确定Brd4抑制的体内靶向性 纤维化症。这项研究的结果将对我们理解这一角色产生重大影响 Brd4在IPF病理生物学中的表观遗传调控作用。