Mechanism of heterochromatin assembly and oncogenic histone mutations

异染色质组装和致癌组蛋白突变的机制

基本信息

批准号：
10591133
负责人：
Songtao Jia
金额：
$ 1.59万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-07 至 2023-07-31
项目状态：
已结题

项目摘要

Project Summary Covalent modifications of histones, such as acetylation, methylation, phosphorylation, and ubiquitylation, are essential regulators of chromatin structure and function. Defects in the regulation of these modifications have causal roles in numerous developmental disorders and diseases. However, the mechanisms that target histone-modifying enzymes to specific genomic locations and regulate their enzymatic activities are not well understood. Our long-term goal is to understand how diverse histone modification activities are coordinated to initiate and maintain different epigenetic states using heterochromatin assembly and oncogenic histone mutations as experimental models. Heterochromatin preferentially assembles at repetitive DNA elements and it is essential for the regulation of gene expression and the maintenance of genome integrity. Formation of heterochromatin is critically dependent on the methylation of H3 lysine 9 (H3K9), and it is generally assumed that precise targeting of histone H3K9 methyltransferases confines heterochromatin to specific genomic regions. However, our recent studies demonstrate that in fission yeast the targeting of H3K9 methyltransferases Clr4 is not very precise, and cells rely critically on negatively regulators, such as the Mst2 histone acetyltransferase and the Epe1 histone demethylase, to remove heterochromatin at inappropriate locations. We will therefore analyze the molecular functions of Mst2 and Epe1 in heterochromatin formation, and examine how their activities change in response to environmental signals to regulate heterochromatin dynamics. Recent high throughput sequencing analyses discovered high incidences of somatic histone lysine-to- methionine (K-to-M) mutations in multiple cancers. These mutations block the methylation of wild type histones. However, the molecular details by which these mutations function are poorly understood and are highly controversial. We have established fission yeast models in which the introduction of H3K9M or H3K36M transgenes abolished the methylation of corresponding lysines on wild type histones, similar to the effects of these mutations in mammalian systems. We will examine how these mutations regulate cellular functions and identify pathways that can be targeted to selectively kill cells containing K-to-M mutations. The ultimate goal of these studies is a complete understanding of how histone methylations are regulated and how their mutations and dysregulation contribute to human diseases.

项目概要组蛋白的共价修饰，例如乙酰化、甲基化、磷酸化和泛素化，染色质结构和功能的重要调节因子。这些修改的监管缺陷在许多发育障碍和疾病中起因果作用。然而，针对的机制将组蛋白修饰酶修饰到特定的基因组位置并调节其酶活性尚不完善明白了。我们的长期目标是了解不同的组蛋白修饰活动如何协调使用异染色质组装和致癌组蛋白启动和维持不同的表观遗传状态突变作为实验模型。异染色质优先在重复 DNA 元件处组装，对于调节基因表达和基因组完整性的维持。异染色质的形成至关重要依赖于 H3 赖氨酸 9 (H3K9) 的甲基化，并且通常认为精确靶向组蛋白 H3K9 甲基转移酶将异染色质限制在特定的基因组区域。然而，我们最近研究表明，在裂殖酵母中，H3K9 甲基转移酶 Clr4 的靶向不是很精确，并且细胞严重依赖负调节因子，例如 Mst2 组蛋白乙酰转移酶和 Epe1 组蛋白去甲基化酶，去除不适当位置的异染色质。因此我们将分析分子 Mst2 和 Epe1 在异染色质形成中的功能，并检查它们的活性如何响应而变化环境信号来调节异染色质动力学。最近的高通量测序分析发现体细胞组蛋白赖氨酸转化为高发生率多种癌症中的蛋氨酸（K-to-M）突变。这些突变阻止野生型组蛋白的甲基化。然而，人们对这些突变发挥作用的分子细节知之甚少，并且高度关注。有争议的。我们建立了裂殖酵母模型，其中引入H3K9M或H3K36M 转基因消除了野生型组蛋白上相应赖氨酸的甲基化，类似于哺乳动物系统中的这些突变。我们将研究这些突变如何调节细胞功能并确定可选择性杀死含有 K-to-M 突变的细胞的途径。这些研究的最终目标是全面了解组蛋白甲基化是如何调控和它们的突变和失调如何导致人类疾病。