Role of Set1-mediated methylation in chromatin function

Set1 介导的甲基化在染色质功能中的作用

基本信息

批准号：
7161311
负责人：
SCOTT D BRIGGS
金额：
$ 25.53万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7161311
关键词：
Acetylation Address Animals Antibodies Applications Grants Biochemical Biochemical Genetics Biological Chromatin Chromosomal translocation Co-Immunoprecipitations Complex Data Disruption Environment Enzymes Exhibits Gene Deletion Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Goals Histone H3 Histones Homologous Gene Human Individual Insecta Laboratories Lead Letters Lysine MLL2 gene Malignant Neoplasms Maps Mass Spectrum Analysis Mediating Methods Methylation Methyltransferase Modification Molecular Molecular Profiling Mono-S Mutation Organism Peptides Phosphorylation Plants Post-Translational Protein Processing Postdoctoral Fellow Proteins Reagent Regulation Research Research Personnel Role SET Domain Saccharomyces cerevisiae Saccharomycetales Site Transcriptional Activation Ubiquitination Western Blotting Yeasts deletion analysis histone methyltransferase human disease in vivo insight mutant novel programs protein protein interaction research study

项目摘要

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）：染色质的动态调控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/或甲基化等翻译后修饰是调节染色质环境和基因表达谱的机制。许多组蛋白修饰活性一旦受到破坏（即突变、扩增和染色体易位），就会与人类癌症相关。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。该提案的长期目标是了解 Set1、芽殖酵母组蛋白 H3 Lys4 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，我们将结合分子、生化和遗传学方法来确定 Set1 相关蛋白在组蛋白甲基化中的重要性，识别新的 Set1 相关蛋白，并表征调节甲基转移酶活性的 Set1 功能域。了解 Set1 和 Set1 相关蛋白的基本功能以及它们如何介导 H3 Lys4 甲基化将为 Set1 如何介导基因调控（例如转录激活、延伸和/或沉默）提供进一步的机制见解。最后，我们预测我们的研究结果将产生广泛的影响，因为许多含有 SET 结构域的蛋白质存在于其他生物体中，如植物、昆虫和动物。此外，存在多种 Set1 H3 Lys4 甲基转移酶人类同源物（例如 MLL1、MLL2 和 Set9）并且与癌症相关。因此，了解 Set1 在酵母中的功能可能为了解包含 SET 结构域的甲基转移酶如何导致癌症等人类疾病提供关键见解。