Gene-specific responses to NF-kB through lysine and arginine methylation of p65

通过 p65 的赖氨酸和精氨酸甲基化对 NF-kB 进行基因特异性反应

基本信息

批准号：
10016329
负责人：
Tao Lu
金额：
$ 29.92万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016329
关键词：
Acute Renal Failure with Renal Papillary Necrosis Affect Affinity Antibodies Arginine Binding Binding Proteins Biological Biological Assay Cardiovascular Diseases Cells ChIP-seq Complex DNA DNA Binding DNA Sequence Development Diabetes Mellitus Disease Doctor of Philosophy Ensure Enzymes Event Experimental Models F Box Domain Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Histones Immune response Immunofluorescence Immunologic Individual Inflammation Interleukin-1 beta Kinetics Knock-in Lead Ligation Link Lung diseases Lysine Malignant Neoplasms Mass Spectrum Analysis Methods Methylation Methyltransferase Modification Molecular NF-kappa B National Institute of General Medical Sciences Nature Nuclear Nuclear Receptors Pathologic Pathology Pharmaceutical Preparations Protein-Arginine N-Methyltransferase Proteins Regulation Regulatory Pathway Response Elements Roentgen Rays SET Domain Series Site Stress Structure Techniques Testing Therapeutic Therapeutic Intervention Tissue-Specific Gene Expression Western Blotting Work base biophysical techniques chromatin immunoprecipitation chronic inflammatory disease experimental study genetically modified cells inducible gene expression innovation insight leucine-rich repeat protein mutant novel novel strategies novel therapeutics p65 physical property preference promoter receptor binding recruit response transcription factor

项目摘要

NIGMS RO1, PI: Tao Lu, Ph.D. Title: Gene-specific responses to NF-κB through lysine and arginine methylation of p65 Abstract: Activation of the multi-functional transcription factor nuclear factor κB (NF-κB), a central coordinator of immune responses, is tightly regulated in order to achieve its normal transient activation in response to stress. In many pathologies, NF-κB is activated abnormally, contributing to the development of a variety of disorders, including lung disease, chronic inflammatory diseases, cardiovascular disease, diabetes, and cancer. Thus, drugs that block NF-κB activation could be effective in treating these diseases. Understanding the molecular mechanism of NF-κB activation is the first step toward our long-term goal of identifying novel therapeutics. This proposal focuses on methylation as a novel mechanism ensuring precise control of NF-κB activity at its target genes. Recently, we discovered that lysine residues 218/221 (K218/221) and arginine residue 30 (R30) of the p65 subunit of NF-κB are methylated by histone-modifying enzymes. Our central hypothesis is that p65 R30 and K218/221 methylation differentially regulates NF-κB-dependent gene expression by affecting promoter binding, recruitment of transcriptional modifiers, and the physical properties of the NF-κB:DNA interaction. To test this central hypothesis, we will pursue two specific aims: Aim 1: Dissect the distinct impacts of p65 R30 and K218/221 methylation on the critical molecular events that lead to differential gene regulation. Aim 2: Determine the structural consequences of p65 R30 methylation, and discover the mechanisms of NF-κB-DNA sequence- specific effects on target gene promoters. Significance: The important findings from this study will identify the molecular mechanisms underlying p65 methylation-dependent gene-specific regulation, thus revealing how the extreme plasticity of biological responses is regulated by NF-κB, and offering deep insights into the development of NF-κB-associated diseases as well as innovative strategies for their therapeutic intervention.

NIGMS RO1，PI：陆涛，博士标题：p65 赖氨酸和精氨酸甲基化对 NF-κB 的基因特异性反应抽象的：多功能转录因子核因子 κB (NF-κB) 的激活，这是免疫的中央协调子在许多情况下，反应受到严格调节，以实现其正常的短暂激活以应对压力。在病理学中，NF-κB 被异常激活，导致多种疾病的发生，包括因此，药物可以预防肺部疾病、慢性炎症、心血管疾病、糖尿病和癌症。阻断 NF-κB 激活可以有效治疗这些疾病的分子机制。 NF-κB 激活的研究是我们实现确定新疗法这一长期目标的第一步。专注于甲基化作为一种新机制，确保精确控制其靶基因的 NF-κB 活性。最近，我们发现p65的赖氨酸残基218/221（K218/221）和精氨酸残基30（R30） NF-κB 亚基被组蛋白修饰酶甲基化。我们的中心假设是 p65 R30 和 p65 R30。 K218/221 甲基化通过影响启动子结合来差异调节 NF-κB 依赖性基因表达，转录修饰剂的招募以及 NF-κB:DNA 相互作用的物理特性来测试这一点。中心假设，我们将追求两个具体目标：目标 1：剖析 p65 R30 和 K218/221 的不同影响导致差异基因调控的关键分子事件的甲基化。 p65 R30 甲基化的结构后果，并发现 NF-κB-DNA 序列的机制 - 对靶基因启动子的特异性影响意义：这项研究的重要发现将确定 p65 甲基化依赖性基因特异性调控的分子机制，从而揭示 p65 甲基化依赖性基因特异性调控的分子机制生物反应的极端可塑性由 NF-κB 调节，并为发展提供深入的见解 NF-κB 相关疾病及其治疗干预的创新策略。