Role of Set1-mediated methylation in chromatin functioin

Set1 介导的甲基化在染色质功能中的作用

• 批准号: 7028127
• 负责人: SCOTT D BRIGGS
• 金额: $ 27.53万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028127
• 关键词: Saccharomyces cerevisiae; binding sites; chromatin; enzyme activity; enzyme inhibitors; fungal genetics; fungal proteins; gene deletion mutation; gene expression; genetic mapping; histones; immunoprecipitation; mass spectrometry; methylation; methyltransferase; protein protein interaction; protein purification; protein quantitation /detection; protein structure function; western blottings

DESCRIPTION (provided by applicant): The dynamic regulation of chromatin serves as an important mechanism for gene regulation. Many studies have demonstrated that posttranslational modification such as acetylation, phosphorylation, ubiquitination, and/or methylation of histones is a mechanism that regulates the chromatin environment and gene expression profiles. Many of these histone modifying activities, when disrupted (i.e., mutations, amplifications and chromosomal translocations), are associated with human cancers. Therefore, studying the machinery that mediates these modifications will provide us with a better understanding of how eukaryotic genomes are regulated and how mis-regulation of these modifying activities can lead to human diseases. The long-term objective of this proposal is to understand the biological role of Set1, the budding yeast histone H3 Lys4 methyltransferase, and its associated proteins in gene regulation. To achieve this goal we will use a combination of molecular, biochemical and genetic approaches to determine the importance of Set1-associated proteins in histone methylation, identify novel Set1-associated proteins, and characterize the functional domains of Set1 that regulate methyltransferase activity. Understanding the basic function of Set1 and Set1-associated proteins and how they mediate H3 Lys4 methylation will provide further mechanistic insight into how Set1 mediates gene regulation such as transcriptional activation, elongation and/or silencing. Finally, we predict that results from our studies will have wide implications since many SET domain-containing proteins exist in other organisms such as plants, insects and animals. Furthermore, several Set1 H3 Lys4 methyltransferase human homologues exist (e.g., MLL1, MLL2, and Set9) and have been associated with cancers. Therefore, understanding how Set1 functions in yeast may provide key insights into understanding how SET domain-containing methyltransferases lead to human diseases such as cancer.

描述（申请人提供）：染色质的动态调节是基因调控的重要机制。许多研究表明，组蛋白的乙酰化、磷酸化、泛素化和甲基化等翻译后修饰是调节染色质环境和基因表达谱的一种机制。许多这些组蛋白修饰活性，当被破坏时（即，突变、扩增和染色体易位）与人类癌症相关。因此，研究介导这些修饰的机制将使我们更好地了解真核生物基因组是如何调节的，以及这些修饰活动的错误调节如何导致人类疾病。这项提案的长期目标是了解Set 1，芽殖酵母组蛋白H3 Lys 4甲基转移酶及其相关蛋白在基因调控中的生物学作用。为了实现这一目标，我们将使用分子，生物化学和遗传学的方法相结合，以确定组蛋白甲基化的重要性Set 1相关蛋白，确定新的Set 1相关蛋白，并表征Set 1的功能域，调节甲基转移酶活性。了解Set 1和Set 1相关蛋白的基本功能以及它们如何介导H3 Lys 4甲基化，将进一步深入了解Set 1如何介导基因调控，如转录激活，延伸和/或沉默。最后，我们预测我们的研究结果将具有广泛的意义，因为许多含SET结构域的蛋白质存在于其他生物，如植物，昆虫和动物中。此外，存在几种Set 1 H3 Lys 4甲基转移酶人同源物（例如，MLL 1、MLL 2和Set 9），并与癌症相关。因此，了解Set 1在酵母中的功能可能会为理解SET结构域甲基转移酶如何导致人类疾病（如癌症）提供关键见解。