Function of Protein Methylation in Chromatin and Signaling Regulation

蛋白质甲基化在染色质中的功能和信号传导调控

• 批准号: 10580699
• 负责人: Or P. Gozani
• 金额: $ 66.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580699
• 关键词: Biochemical; Biological Process; Biology; Cell model; Cell physiology; Cellular biology; Chromatin; Disease; Enzymes; Epigenetic Process; Gene Expression; Genomics; Goals; Health; Histidine; Histone H3; Homeostasis; Human; Human Genome; Link; Lysine; Malignant Neoplasms; Mammalian Cell; Methylation; Methyltransferase; Modification; Molecular; Mutation; Pathogenesis; Pathology; Physiological; Play; Post-Translational Protein Processing; Protein Methylation; Protein Methyltransferases; Proteins; Proteomics; Regulation; Research; Role; Signal Pathway; Signal Transduction; Source; clinically actionable; gene translocation; histone methylation; human disease; insight; mouse model; multidisciplinary; non-histone protein; protein function

ABSTRACT Covalent post-translational protein modifications (PTMs) contribute to all aspects of cell physiology and are a major source of protein functional diversity in mammalian cells. Aberrant regulation of PTMs is a common feature of human diseases. Our research focuses on two important PTMs: protein methylation at lysine and histidine residues. Our overarching goal is to elucidate at a molecular level the physiologic roles for lysine and histidine methylation signaling in the regulation of chromatin biology, epigenetics and other fundamental biological processes, and to understand how disruption in these mechanisms contributes to human disease. Within this research framework we will investigate the biology and function of enzymes that regulate histone methylation dynamics, with a focus on methylation at histone H3 lysine 36 (H3K36). Beyond histone methylation, there is a growing appreciation that a number of non-histone proteins, including several with clear roles in gene expression and signal transduction are lysine methylated. Indeed, there are likely far greater than one hundred lysine methyltransferases in the human genome, and an increasing number of examples of mutation or translocation of these genes being linked to human disorders. Thus, it is likely that deregulation in non-histone protein methylation homeostasis plays a crucial role in disease pathogenesis. We will explore the biology and function of new enzymes and non-histone protein methylation signaling pathways. In addition to lysine methylation, other residues like histidine are also methylated; though relatively little is known about the histidine methylation modification network. We will explore the hypothesis that protein histidine methylation has an underappreciated and significant role in signal transduction, cell biology, and disease pathogenesis. For our studies, we will use a multi-disciplinary strategy that include biochemical, molecular, proteomic, genomic, cellular and mouse modeling approaches.

摘要 共价翻译后蛋白质修饰（PTM）有助于细胞生理学的各个方面，是一种重要的生物学机制。 哺乳动物细胞中蛋白质功能多样性的主要来源。PTM的异常调节是一种常见的 人类疾病的特征。我们的研究集中在两个重要的PTM：赖氨酸的蛋白质甲基化和 组氨酸残基。我们的首要目标是在分子水平上阐明赖氨酸和 组氨酸甲基化信号在调节染色质生物学、表观遗传学和其他基础 生物过程，并了解这些机制的破坏如何导致人类疾病。 在这个研究框架内，我们将研究调节组蛋白的酶的生物学和功能 甲基化动力学，重点是组蛋白H3赖氨酸36（H3 K36）的甲基化。超越组蛋白 由于甲基化，越来越多的人认识到许多非组蛋白蛋白，包括几种具有明显甲基化的蛋白质， 在基因表达和信号转导中的作用是赖氨酸甲基化。或许，更大的可能是， 人类基因组中的100种赖氨酸甲基转移酶，以及越来越多的 这些基因的突变或易位与人类疾病有关。因此，很可能放松管制， 非组蛋白甲基化稳态在疾病发病机制中起着至关重要的作用。我们将探讨 新酶和非组蛋白甲基化信号通路的生物学和功能。除了 赖氨酸甲基化，其他残基如组氨酸也被甲基化;尽管对赖氨酸甲基化的了解相对较少。 组氨酸甲基化修饰网络。我们将探讨蛋白质组氨酸甲基化 在信号转导、细胞生物学和疾病发病机制中的重要作用未被充分认识。为我们 研究，我们将使用多学科的战略，包括生物化学，分子，蛋白质组学，基因组学， 细胞和小鼠建模方法。