Investigating chromatin mechanisms using viral systems

使用病毒系统研究染色质机制

• 批准号: 10386678
• 负责人: Daphne Christina Avgousti
• 金额: $ 12.5万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386678
• 关键词: 3-Dimensional; Adenovirus Protein; Adenoviruses; Area; Binding; Biological; Biological Process; Biology; Cells; Chromatin; Chromosomes; Development; Disease; Genome; Goals; Herpesviridae; Histones; Infection; Inflammation; Innovative Therapy; Malignant Neoplasms; Molecular Biology; Molecular Conformation; Nuclear; Positioning Attribute; Proteins; RNA Splicing; Regulation; Simplexvirus; System; TP53 gene; Technology; Testing; Variant; Viral; Viral Packaging; Virus; Virus Diseases; cancer therapy; dynamic system; parent grant; pathogen; virus host interaction

PROJECT SUMMARY (as stated in parent grant) All eukaryotic genomes are compacted in a fundamental assembly called chromatin, the aberrant regulation of which is a hallmark of many diseases and cancers. Technologies to study chromatin have advanced significantly in recent years, allowing us to progress from linear sequencing to 3D chromosome conformation studies. However, it is becoming increasingly clear that chromatin states are dynamic and respond to perturbations. Thus a barrier remains to understanding the biological functions of chromatin in a dynamic system, and not merely at the baseline state. Viruses have evolved to take over the cell to produce viral progeny, necessarily hijacking cellular chromatin for viral benefit, thereby providing an ideal dynamic system in which to interrogate chromatin state changes. Moreover, the study of virus-host interactions has been doubly beneficial by leading to advances in virus biology and to discoveries of some of the most important areas of molecular biology, from splicing to p53. Due to the advances in sequencing technology, we are now ideally positioned to take the next step to understanding chromatin in the context of biological changes. In this proposal, we aim to merge cutting-edge chromatin technology with virus infection to reveal fundamental chromatin functions. We use two different nuclear replicating viruses, adenovirus and herpesvirus, as the test cases for virus infection to pinpoint chromatin vulnerabilities exploited by multiple pathogens. We have identified a viral packaging protein from adenovirus, protein VII, that causes global chromatin reorganization and we will systematically dissect the mechanisms by which this reorganization occurs. Our preliminary results suggest that protein VII, together with cellular binding partners, may replace linker histones thus revealing a previously unknown vulnerability of chromatin. We have also uncovered that herpes simplex virus incorporates the histone variant macroH2A1 on its genome during infection. MacroH2A1 has been described as a marker of both silencing and an activating chromatin, therefore, we will use this scenario to untangle the long-standing enigma of macroH2A1 function. Completion of the proposed studies will generate new chromatin targets and facilitate development of innovative therapies for cancer, inflammation, and viral diseases.

项目摘要 (as（见父母补助金） 所有真核生物的基因组都被压缩在一个称为染色质的基本组装中， 这是许多疾病和癌症的标志。研究染色质的技术已经进步 近年来显着，使我们能够从线性测序进展到3D染色体构象 问题研究然而，越来越清楚的是，染色质状态是动态的，并且响应于染色质状态的变化。 扰动因此，理解染色质在动态细胞中的生物学功能仍然是一个障碍。 系统，而不仅仅是在基线状态。病毒已经进化到接管细胞， 后代，必然劫持细胞染色质的病毒的好处，从而提供了一个理想的动态系统， 用来询问染色质状态的变化。此外，病毒与宿主相互作用的研究也受到了双重关注。 有益的是导致病毒生物学的进步，并发现一些最重要的领域， 分子生物学，从剪接到p53。由于测序技术的进步，我们现在理想地 定位采取下一步了解染色质在生物变化的背景下。在这 我们的目标是将尖端的染色质技术与病毒感染相结合，以揭示基本的 染色质功能我们使用两种不同的核复制病毒，腺病毒和疱疹病毒， 病毒感染的病例，以查明被多种病原体利用的染色质漏洞。我们有 从腺病毒中鉴定出一种病毒包装蛋白，即蛋白VII，它能引起整体染色质重组 我们将系统地剖析这种重组发生的机制。我们的初步结果 提示蛋白VII与细胞结合伴侣一起，可能取代连接组蛋白，从而揭示了 以前未知的染色质的脆弱性。我们还发现单纯疱疹病毒 在感染过程中其基因组上的组蛋白变体macroH2A1。MacroH2A1已被描述为 沉默和激活染色质，因此，我们将使用这种情况来解开长期存在的 macroH2A1功能之谜完成拟议的研究将产生新的染色质靶点， 促进癌症、炎症和病毒性疾病的创新疗法的开发。