Regulation of non-histone protein function by lysine methylation

赖氨酸甲基化对非组蛋白功能的调节

• 批准号: 10707982
• 负责人: Evan Mitchell Cornett
• 金额: $ 39.57万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707982
• 关键词: Biochemistry; Biological Process; Cell physiology; Cells; Chromatin; Enzymes; Genomics; Goals; Histones; Human; Lysine; Maps; Mass Spectrum Analysis; Methods; Methylation; Methyltransferase; Neuronal Differentiation; Physiological; Post-Translational Protein Processing; Process; Proteins; Proteome; Proteomics; Regulation; Research; Resolution; Signal Transduction; Substrate Specificity; circadian; circadian pacemaker; developmental disease; human disease; methylome; non-histone protein; protein function

PROJECT SUMMARY: Reversible lysine methylation is well understood to regulate histone proteins and chromatin templated processes. Dysregulation of the enzymes responsible for adding (lysine methyltransferases) and removing (lysine demethylases) lysine methylation is directly associated with many human diseases. In addition to histone proteins, thousands of non-histone proteins in the human proteome contain lysine methylation, yet we still understand very little about the function of non-histone lysine methylation. Our long-term goal is to understand how lysine methylation regulates non-histone protein function and cellular processes. Within this broad framework, we strive to identify biological processes that are regulated by lysine methylation, the substrate specificity of KMTs and KDMs, and how dysregulation of lysine methylation signaling contributes to human disease and developmental disorders. Toward this goal, we recently developed a functional proteomics platform to profile the substrate selectivity of KMTs and successfully used it to identify the circadian regulator PER2 as a substrate of lysine methyltransferase SMYD2. We also recently optimized a mass spectrometry pipeline for high- resolution mapping of lysine methylation. Over the next five years, we will build on this progress and use these new methods in projects that seek to answer three fundamental questions in the context of the circadian clock and neuronal differentiation: How big is the lysine methylome? What are the physiologically relevant substrates for KMTs/KDMs? And what is the function of non-histone lysine methylation? We will answer these questions by leveraging our strengths in biochemistry, proteomics, genomics, and cell-based studies, to expand our basic mechanistic understanding of the function of lysine methylation in cellular processes.

项目概要： 可逆的赖氨酸甲基化被充分理解为调节组蛋白和染色质模板化过程。 负责添加（赖氨酸甲基转移酶）和去除（赖氨酸）的酶调节异常 脱甲基酶）赖氨酸甲基化与许多人类疾病直接相关。除了组蛋白 蛋白质，人类蛋白质组中成千上万的非组蛋白蛋白质含有赖氨酸甲基化，但我们仍然 对非组蛋白赖氨酸甲基化的功能知之甚少。我们的长期目标是了解 赖氨酸甲基化如何调节非组蛋白功能和细胞过程。在这个广阔的 框架，我们努力确定由赖氨酸甲基化调节的生物过程， KMT和KDM的特异性，以及赖氨酸甲基化信号传导的失调如何有助于人类 疾病和发育障碍。为了实现这一目标，我们最近开发了一个功能蛋白质组学平台， 分析KMT的底物选择性，并成功地将其用于鉴定昼夜节律调节因子PER 2作为一种生物调节因子。 赖氨酸甲基转移酶SMYD 2的底物。我们最近还优化了一个质谱分析管道，用于高- 赖氨酸甲基化的分辨率作图。在今后五年中，我们将在这一进展的基础上， 在生物钟的背景下，寻求回答三个基本问题的项目中的新方法 和神经元分化：赖氨酸甲基化有多大？什么是生理相关的底物 KMT/KDM？非组蛋白赖氨酸甲基化的作用是什么？我们将回答这些问题， 利用我们在生物化学，蛋白质组学，基因组学和基于细胞的研究方面的优势，扩大我们的基础 对赖氨酸甲基化在细胞过程中的功能的机械理解。