Role of Set2 and H3 methylation in chromatin function

摘要 组蛋白甲基化是染色质组织和基因调控的基础 转录。我们将继续我们的长期目标，阐明赖氨酸特异性组蛋白是如何在细胞中表达的。 甲基转移酶调节基因表达并促进细胞发育和疾病。 我们为这个目标建立的模型是确定Set 2甲基转移酶的功能， 催化H3赖氨酸36甲基化（H3 K36 me）。我们和其他人已经证明，Set 2通过一个 与延伸RNA聚合酶II结合，以募集各种染色质修饰活性， 维持抑制染色质状态的基因，其抵抗普遍转录和组蛋白 交易所Set 2对细胞生理学的重要性被以下事实所强调： Set 2的同源物SETD 2是癌症中最常见的突变蛋白之一，与p53相当 和RB。尽管Set 2的重要性，我们对它的沉积和去除知之甚少。 染色质标记有助于细胞生物学。关于H3 K36甲基化的不完整知识 我们的初步发现不仅揭示了Set 2在控制细胞中的作用， 循环，但存在一种新的H3 K36去甲基化酶，可以调节基因转录，通过 维持启动子去甲基化。我们假设，转录保真度的调节， Set 2/H3 K36 me对于细胞周期进程所需的精确转录程序至关重要。 我们还假设Ecm 5是一种H3 K36特异性的去甲基化酶，其功能是维持启动子 由复合物Ecm 5靶向的基因的功能发现于。通过确定Set 2/H3 K36 me 功能，我们将消除显着的缺陷，在染色质功能的理解。

ABSTRACT Histone methylation is fundamental to the organization of chromatin and in the regulation of gene transcription. We will continue our long-term goal of elucidating how lysine-specific histone methyltransferases regulate gene expression and contribute to cellular development and disease. Our established model for this goal is determining the functions of the Set2 methyltransferase, which catalyzes H3 lysine 36 methylation (H3K36me). We and others have shown that Set2 functions through an association with elongating RNA polymerase II to recruit a variety of chromatin-modifying activities to genes that maintain a suppressed chromatin state resistant to pervasive transcription and histone exchange. The significance of Set2 to cellular physiology is underscored by the fact that the human homolog of Set2, SETD2, is one of the most frequently mutated proteins in cancer, comparable with p53 and RB. Despite the significance of Set2, we know little about how the deposition and removal of this chromatin mark contributes to cellular biology. This incomplete knowledge about H3K36 methylation function is exemplified by our preliminary findings that reveal not only a role for Set2 in control of the cell cycle, but the existence of a novel H3K36 demethylase that may regulate gene transcription through maintaining promoter demethylation. We hypothesize that the regulation of transcription fidelity by Set2/H3K36me is critical for the precise transcription programs necessary for cell cycle progression. We also hypothesize that Ecm5 is a H3K36-specific demethylase that functions to maintain promoter function of genes targeted by the complex Ecm5 is found in. By determining how Set2/H3K36me functions, we will eliminate significant deficiencies in the understanding of chromatin function.