Role of Set1-mediated methylation in chromatin functioin

染色质的动态调控是基因调控的重要机制。许多 研究表明，翻译后修饰，如乙酰化、磷酸化、 组蛋白的泛素化和/或甲基化是调节染色质的一种机制 环境和基因表达谱。许多这些组蛋白修饰活动，当 被破坏(即突变、扩增和染色体易位)与 人类癌症。因此，研究调节这些变化的机制将提供 让我们更好地了解真核基因组是如何调控的，以及如何错误地调控 这些修饰活动可能会导致人类疾病。这项提议的长期目标是 为了了解萌芽酵母组蛋白H3裂解4甲基转移酶Set1的生物学作用，以及 其在基因调控中的相关蛋白。为了实现这一目标，我们将结合使用 确定Set1相关重要性的分子、生化和遗传学方法 组蛋白甲基化中的蛋白质，鉴定新的Set1相关蛋白质，并表征 调节甲基转移酶活性的Set1功能结构域。了解基本知识 Set1和Set1相关蛋白的功能及其在H3Lys4甲基化中的作用 提供对Set1如何介导基因调控的进一步机械性见解，如转录 激活、延长和/或沉默。最后，我们预测我们的研究结果将会有 广泛的含义，因为许多包含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，几种Set1 H3裂解4甲基转移酶人 同系物存在(例如，MLL1、MLL2和Set9)，并且与癌症有关。 因此，了解Set1在酵母中的功能可能会为理解 SET-含结构域甲基转移酶如何导致癌症等人类疾病。

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.