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

项目摘要： 多功能转录因子核因子κ B（NF-κ B）的激活，是免疫调节的中心协调者， 反应，是严格调节，以实现其正常的瞬态激活响应压力。在许多 在病理学中，NF-κ B被异常激活，导致多种疾病的发展，包括 肺病、慢性炎症性疾病、心血管疾病、糖尿病和癌症。因此， 阻断NF-κ B活化可能是治疗这些疾病的有效方法。了解的分子机制 NF-κ B的激活是我们实现长期目标的第一步，即确定新的治疗方法。这项建议 关注甲基化作为一种新的机制，确保精确控制NF-κ B在其靶基因的活性。 最近，我们发现p65蛋白的赖氨酸残基218/221（K218/221）和精氨酸残基30（R30）与p65蛋白的氨基酸残基218/221（K218/221）和精氨酸残基30（R30）的氨基酸残基218/221（K218/221）的氨基酸残基218/221（R30）的氨基酸残基218/221（K218/221）的氨基酸残基218/221（K218/221）的氨基酸残基218/221（K218/221）和精氨酸残基221（R30）的氨基酸残基218/221（R30）的氨基酸残基218/221（R30）的氨基酸残基218/2221（R30）的氨基酸残基218/2221 NF-κ B亚基被组蛋白修饰酶甲基化。我们的中心假设是p65 R30和 K218/221甲基化通过影响启动子结合差异调节NF-κ B依赖性基因表达， 转录调节因子的募集以及NF-κ B：DNA相互作用的物理性质。为了验证这一 中心假设，我们将追求两个具体的目标：目标1：剖析p65 R30的不同影响， K218/221甲基化对导致差异基因调控的关键分子事件的影响。目标2：确定 p65 R30甲基化的结构后果，并发现NF-κ B-DNA序列的机制 对靶基因启动子的特异性作用。意义：这项研究的重要发现将确定 p65甲基化依赖的基因特异性调控的分子机制，从而揭示了 NF-κ B调控着生物反应的高度可塑性，这为深入了解NF-κ B的发展提供了新的视角。 NF-κ B相关疾病及其治疗干预的创新策略。

Project 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.