Mechanism of Heterochromatin Assembly and epigenetic inheritance

异染色质组装和表观遗传机制

基本信息

批准号：
10619175
负责人：
Songtao Jia
金额：
$ 41.21万
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 2028-07-31
项目状态：
未结题

项目摘要

Project Summary Covalent modifications of histones, such as acetylation, methylation, phosphorylation, and ubiquitylation, are essential for regulating chromatin structure and function and defective histone modifications have causal roles in numerous developmental disorders and diseases. Our long-term goal is to use fission yeast heterochromatin assembly as an experimental model to study how diverse histone modification activities are coordinated to initiate different gene expression states and how these states are epigenetically inherited. Heterochromatin preferentially assembles at repetitive DNA elements, and it is essential for regulating gene expression and maintaining genome integrity. The formation of heterochromatin is critically dependent on the methylation of H3 lysine 9 (H3K9me). Interestingly, the activities of H3K9 methyltransferases are stimulated by the ubiquitylation of H3 lysine 14 (H3K14ub), although the mechanism is poorly understood. We will examine how H3K14ub stimulates H3K9 methyltransferases and how H3K14ub is regulated in vivo to aid heterochromatin assembly. Heterochromatin is also a great model to study chromatin-based mechanisms of epigenetic inheritance. An important unresolved question is how parental histones carrying modifications are deposited onto newly synthesized DNA during the S phase of the cell cycle to direct the duplication of these modifications on daughter chromatids. We developed eSPAN (enrichment of Sequencing Protein-Associated Nascent DNA) in fission yeast, which allows us to measure the segregation of parental histones on daughter DNA strands. We will integrate this new genomic tool and traditional genetic approaches to examine mechanisms that regulate the segregation of parental histones and how they contribute to epigenetic inheritance. Together, these studies will address fundamental questions about how histone modifications are regulated and inherited, and how their dysregulation contributes to human diseases.

项目摘要组蛋白的共价修饰，例如乙酰化，甲基化，磷酸化和泛素化是调节染色质结构和功能以及缺陷组蛋白的修饰至关重要在许多发育障碍和疾病中。我们的长期目标是使用裂变酵母异染色质组装作为一个实验模型，以研究如何协调各种组蛋白修饰活动启动不同的基因表达状态以及这些状态如何表观遗传遗传。异染色质优先组装在重复的DNA元件下，这对于调节基因表达和维持基因组完整性。异染色质的形成主要取决于H3的甲基化赖氨酸9（H3K9ME）。有趣的是，泛素化刺激H3K9甲基转移酶的活性 H3赖氨酸14（H3K14UB）的理解很少。我们将研究H3K14UB如何刺激H3K9甲基转移酶以及如何在体内调节H3K14UB以帮助异染色质组装。异染色质也是研究基于染色质的表观遗传机制的重要模型。一个重要的未解决的问题是如何将携带修饰的父母组蛋白沉积到新的在细胞周期的S阶段合成DNA，以指导这些修饰的重复女儿染色单体。我们开发了ESPAN（富集了测序蛋白相关的新生DNA）裂变酵母，这使我们能够测量子DNA链上亲本组蛋白的分离。我们将整合这种新的基因组工具和传统的遗传方法，以检查调节调节的机制父母组蛋白的分离及其如何促进表观遗传。在一起，这些研究将解决有关如何调节和继承组蛋白修饰的基本问题，以及如何失调会导致人类疾病。