Mechanism of heterochromatin assembly

异染色质组装机制

基本信息

批准号：
8694896
负责人：
Songtao Jia
金额：
$ 32.33万
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：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694896
关键词：
Acetylation Affect Animal Model Beryllium Binding Biochemical Bypass Cancer Biology Cancer Patient Cells Centromere Chromatin Chromatin Structure Chromosome Segregation Chromosome Structures Complex Coupled DNA DNA biosynthesis DNA-Directed RNA Polymerase Data Defect Development Disease Elements Ensure Enzymes Epigenetic Process Feedback Fission Yeast Gene Expression Gene Expression Profile Gene Silencing Generations Genetic Genetic Materials Genetic Recombination Genetic Transcription Genome Genomics Goals Heterochromatin Histones Human Investigation Location Maintenance Malignant Neoplasms Mating Types Mediating Meiosis Methylation Methyltransferase Mitosis Modeling Modification Molecular Mutation Organism Pathway interactions Phenocopy Phosphorylation Play Positioning Attribute Process Proteins RNA Interference RNA Interference Pathway Recruitment Activity Regulation Repetitive Sequence Role Site Small Interfering RNA Structure Suppressor Mutations Tertiary Protein Structure Testing Transcript Tumor-Suppressor Gene Inactivation base developmental disease histone acetyltransferase histone modification insight mutant public health relevance research study segregation telomere tumor progression

项目摘要

DESCRIPTION (provided by applicant): 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. Heterochromatin preferentially assembles at repetitive DNA elements. It is critical for setting up gene expression patterns during development and maintaining genome integrity by rendering repetitive structures recombinationally inert. It is also crucial for functional organization of vital chromosomal structures such as centromeres and telomeres, ensuring the accurate segregation of genetic material during mitosis and meiosis. Heterochromatin formation requires the concerted actions of diverse histone modifying enzymes as well as the RNA interference (RNAi) machinery. Paradoxically, transcription of the underlying repetitive DNA elements is also required for proper heterochromatin assembly, although heterochromatin generally represses transcription. These transcripts not only serve as substrates for RNAi to produce small interfering RNAs (siRNAs), but also as a platform for the recruitment of histone-modifying enzymes through siRNA-containing effector complexes. Histone modifications in turn stabilize the binding of the RNAi machinery to heterochromatin. As a result, processing of transcripts by RNAi and recruitment of histone modifying activities are tightly coupled, making it difficult to identify the initial signas that target repetitive regions for heterochromatin assembly. We have recently discovered that loss of a number of factors allows cells to bypass the requirement of the RNAi machinery for heterochromatin assembly. Our studies of the one class of these factors, the Mst2 histone acetyltransferase complex, revealed that reducing RNA polymerase recruitment to heterochromatin during DNA replication is essential for the inheritance of the heterochromatic state through generations. The goal of this proposal is to further understand how loss of diverse activities could bypass the RNAi requirement for heterochromatin assembly. These analyses will provide molecular mechanisms of how heterochromatin-promoting activities are regulated to control the initiation, spreading, and maintenance of heterochromatin domains.

描述（由申请人提供）：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重要调节因子。这些修饰的调节缺陷在许多发育障碍和疾病中具有因果作用。然而，将组蛋白修饰酶靶向特定基因组位置并调节其酶活性的机制尚不清楚。我们的长期目标是了解不同的组蛋白修饰活动如何协调以启动和维持不同的表观遗传状态。异染色质优先在重复的 DNA 元件处组装。它对于在发育过程中建立基因表达模式以及通过使重复结构具有重组惰性来维持基因组完整性至关重要。它对于着丝粒和端粒等重要染色体结构的功能组织也至关重要，确保有丝分裂和减数分裂过程中遗传物质的准确分离。异染色质的形成需要多种组蛋白修饰酶以及 RNA 干扰 (RNAi) 机制的协同作用。矛盾的是，尽管异染色质通常会抑制转录，但正确的异染色质组装也需要底层重复 DNA 元件的转录。这些转录物不仅作为 RNAi 产生小干扰 RNA (siRNA) 的底物，而且还作为通过含有 siRNA 的效应复合物招募组蛋白修饰酶的平台。组蛋白修饰反过来又稳定了 RNAi 机制与异染色质的结合。因此，RNAi 对转录本的处理和组蛋白修饰活性的募集紧密耦合，使得很难识别针对异染色质组装的重复区域的初始信号。我们最近发现，许多因子的丢失使得细胞能够绕过异染色质组装的 RNAi 机制的要求。我们对其中一类因子（Mst2 组蛋白乙酰转移酶复合物）的研究表明，在 DNA 复制过程中减少 RNA 聚合酶向异染色质的募集对于异染色质状态代代相传至关重要。该提案的目的是进一步了解多种活性的丧失如何绕过异染色质组装的 RNAi 要求。这些分析将提供如何调节异染色质促进活性以控制异染色质结构域的起始、扩散和维持的分子机制。