Investigating chromatin mechanisms using viral systems

使用病毒系统研究染色质机制

• 批准号: 10810299
• 负责人: Daphne Christina Avgousti
• 金额: $ 1.54万
• 依托单位: FRED HUTCHINSON CANCER 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10810299
• 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; Virus Replication; 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.

项目总结