Mechanism of BET Proteins in Th17 Cell Differentiation

BET蛋白在Th17细胞分化中的机制

基本信息

批准号：
9241951
负责人：
Ming-Ming Zhou
金额：
$ 42.38万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-10 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241951
关键词：
Autoimmune Diseases Bees Binding Biological Models Biology Bromodomain CD4 Positive T Lymphocytes Cell Differentiation process Cells ChIP-seq Characteristics Chemicals Chromatin Colitis Complex Cues Deposition Development Disease Disease model Enhancers Ensure Future Gene Expression Gene Expression Profile Gene Order Gene Targeting Genes Genetic Enhancer Element Genetic Transcription Genomics Histones Human Human Biology In Vitro Individual Inflammation Inflammatory Investigation Knowledge Ligands Lysine Malignant Neoplasms Modeling Molecular Mus Pharmacology Phosphorylation Physiological Play Positive Transcriptional Elongation Factor B Protein Family Proteins RNA RNA Polymerase II Recruitment Activity Regulatory T-Lymphocyte Role Site Structure T-Lymphocyte Tertiary Protein Structure Testis Transcription Elongation Transcriptional Activation Transcriptional Regulation Treatment Efficacy Work adaptive immunity biological systems cell type cohesin cytokine design effective therapy epigenetic drug epigenomics gene interaction human disease in vivo inhibitor/antagonist insight new therapeutic target next generation novel novel therapeutic intervention prevent programs promoter public health relevance response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): The bromodomain and extra-terminal domain (BET) family proteins, consisting of Brd2, Brd3, Brd4 and testis-specific Brdt, are widely recognized as major transcriptional regulators in biology, owing to their two characteristic tandem bromodomains (BrDs) binding to activated, lysine-acetylated histones and transcription factors to recruit transcription factors/effectors to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of the BET proteins with pan-BET BrD inhibitors such as JQ1 has been shown to block broadly gene transcription in biology, and human cancer and inflammation disease models. Despite their prominent importance, however, our current knowledge of functional distinctions of the BET proteins has remained elusive, thus seriously hampering their potential as viable epigenetic drug targets for new disease treatment. As such, we propose to determine functional mechanisms of the BET proteins in gene transcriptional regulation in T-helper 17 (Th17) cell differentiation that has bee implicated in inflammatory disorders. Our study is built upon our recent discovery that Brd2 and Brd4 have distinct genomic deposition in Th17 cells, and exert different functions even at genes whose transcription they co-regulate. Importantly, we found that selective inhibition of the first bromodomain of BET proteins using our newly developed BrD inhibitor hinders primarily Th17 cell differentiation with beneficially minimal effects on Th1, Th2 and Treg cells, and also prevents adaptive T-cell transfer-induced colitis in mice. These favorable findings motivate us to determine the detailed molecular mechanisms of Brd2 and Brd4 functions in Th17 cell development, and establish a new therapeutic strategy for inflammatory disorders. Specifically, we aim to achieve three specific aims: (1) determine distinct mechanistic roles of the BET proteins in gene transcription of Th17 cells; (2) develop novel chemical modulators for BET BrDs; and (3) characterize genomic functions of BET proteins in Th17 cell differentiation. We envision our study not only to yield new mechanistic insights into Brd2 and Brd4 functions in transcriptional regulation of Th17 cell development in adaptive immunity, but also provide a clearer direction for developing more effective therapeutic treatment for inflammatory disorders.

描述（由申请人提供）：溴结构域和末端外结构域 (BET) 家族蛋白由 Brd2、Brd3、Brd4 和睾丸特异性 Brdt 组成，由于其两个特征性串联溴结构域，被广泛认为是生物学中的主要转录调节因子(BrD) 与激活的赖氨酸乙酰化组蛋白和转录因子结合，以招募转录因子/效应子至靶基因位点，并激活 RNA 聚合酶 II然而，尽管 JQ1 等泛 BET BrD 抑制剂对 BET 蛋白的药理学抑制具有显着的重要性，但我们目前对它们的了解却有限。 BET 蛋白的功能差异仍然难以捉摸，因此严重阻碍了它们作为新疾病治疗的可行表观遗传药物靶标的潜力，因此，我们建议确定 BET 蛋白在 T 辅助细胞基因转录调控中的功能机制。与炎症性疾病有关的 17 (Th17) 细胞分化是基于我们最近的发现，即 Brd2 和 Brd4 在 Th17 细胞中具有不同的基因组沉积，甚至在它们共同调节转录的基因上发挥不同的功能。我们发现，使用我们新开发的 BrD 抑制剂选择性抑制 BET 蛋白的第一个溴结构域主要阻碍 Th17 细胞分化，对 Th1、Th2 和 Treg 细胞的影响最小，并且还可以防止这些有利的发现促使我们确定 Brd2 和 Brd4 在 Th17 细胞发育中的详细分子机制，并建立针对炎症性疾病的新治疗策略。目标：(1) 确定 BET 蛋白在 Th17 细胞基因转录中的不同机制作用；(2) 开发 BET BrD 的新型化学调节剂；(3) 表征 BET 蛋白在 Th17 细胞分化中的基因组功能。我们希望我们的研究不仅能够对 Brd2 和 Brd4 在适应性免疫中 Th17 细胞发育的转录调控中的功能产生新的机制见解，而且还为开发更有效的炎症性疾病治疗方法提供更明确的方向。