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 研究已经证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机制， 环境和基因表达谱。许多这些组蛋白修饰活动，当 中断（即，突变、扩增和染色体易位），与 人类癌症因此，研究介导这些修改的机制将提供 让我们更好地了解真核生物基因组是如何调节的，以及基因组的错误调节是如何发生的。 这些修饰活性可导致人类疾病。这项建议的长远目标是 了解Set 1的生物学作用，芽殖酵母组蛋白H3 Lys 4甲基转移酶， 其相关蛋白在基因调控中的作用。为了实现这一目标，我们将结合使用 分子，生物化学和遗传学方法来确定Set 1相关的重要性， 组蛋白甲基化的蛋白质，鉴定新的Set 1相关蛋白，并表征 调节甲基转移酶活性的Set 1的功能结构域。了解基本 Set 1和Set 1相关蛋白的功能以及它们如何介导H3 Lys 4甲基化将 提供了进一步的机制洞察如何设置1介导的基因调控，如转录 激活、延长和/或沉默。最后，我们预测，我们的研究结果将有 广泛的影响，因为许多SET结构域含有蛋白质存在于其他生物体， 植物、昆虫和动物此外，几种Set 1 H3 Lys 4甲基转移酶人 存在同源物（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 1在酵母中的作用提供关键的见解。 SET结构域甲基转移酶如何导致人类疾病，如癌症。

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.