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

• 批准号: 9975193
• 负责人: Songtao Jia
• 金额: $ 39.48万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9975193
• 关键词: Acetylation; Animal Model; Cell physiology; Cells; Chromatin Structure; DNA; Defect; Development; Elements; Enzymes; Epigenetic Process; Experimental Models; Fission Yeast; Gene Expression Regulation; Genomic Segment; Genomics; Goals; Heterochromatin; High-Throughput Nucleotide Sequencing; Histone H3; Histones; Incidence; Location; Lysine; Maintenance; Malignant Neoplasms; Methionine; Methylation; Methyltransferase; Modification; Molecular; Mutation; Oncogenic; Pathway interactions; Phosphorylation; Regulation; Role; Signal Transduction; System; Transgenes; Yeast Model System; cancer type; cell killing; developmental disease; genome integrity; histone acetyltransferase; histone demethylase; histone methylation; histone modification; human disease; insight; response; treatment strategy; tumor; tumor progression

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.

项目摘要 组蛋白的共价修饰，例如乙酰化，甲基化，磷酸化和泛素化是 染色质结构和功能的基本调节剂。这些修改的调节中的缺陷具有 在许多发育障碍和疾病中的因果作用。但是，针对的机制 将组蛋白改性酶用于特定的基因组位置并调节其酶活性不好 理解。我们的长期目标是了解多样化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态 突变作为实验模型。 异染色质优先在重复的DNA元素下组装，这对于调节至关重要 基因表达和基因组完整性的维持。异染色质的形成非常重要 取决于H3赖氨酸9（H3K9）的甲基化，通常假定确切的靶向 组蛋白H3K9甲基转移酶将异染色质局限于特定的基因组区域。但是，我们最近 研究表明，在裂变酵母中，H3K9甲基转移酶CLR4的靶向不是很精确，并且 细胞严格依靠负调节剂，例如MST2组蛋白乙酰转移酶和EPE1组蛋白 去甲基酶，在不适当的位置去除异染色质。因此，我们将分析分子 MST2和EPE1在异染色质形成中的功能，并检查其活性如何变化 到调节异染色质动力学的环境信号。 最近的高吞吐量测序分析发现了体细胞蛋白赖氨酸至 - 多种癌症中的蛋氨酸（K-TO-M）突变。这些突变阻断了野生型组蛋白的甲基化。 但是，这些突变功能的分子细节知之甚少，并且很高 有争议的。我们已经建立了裂变酵母模型，其中引入H3K9M或H3K36M 转基因消除了相应赖氨酸在野生型组蛋白上的甲基化，类似于 这些突变在哺乳动物系统中。我们将研究这些突变如何调节细胞功能和 识别可以针对选择性杀死含有K-TO-M突变的细胞的途径。 这些研究的最终目标是完全理解组蛋白甲基化的调节以及 它们的突变和失调如何导致人类疾病。