Mechanisms of oral epigenetic reprogramming in tumorviral pathogenesis

口腔表观遗传重编程在肿瘤病毒发病机制中的机制

基本信息

批准号：
8730747
负责人：
Jennifer Y Webster-Cyriaque
金额：
$ 28.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730747
关键词：
AIDS related cancer AIDS/HIV problem Acetylation Acquired Immunodeficiency Syndrome Affect American Antiviral Agents Antiviral Response Archives Autoimmunity Bacterial Infections Bacteriology Binding Cell Line Cell physiology Cells ChIP-seq Chromatin Computer Analysis DNA DNA Modification Process DNA Polymerase II Data Analyses Disease Disease Progression Elements Enzymes Epigenetic Process Epithelial Epithelial Cells Event Exposure to Gene Expression Genetic Transcription Goals HIV Hairy Leukoplakia Herpesviridae Histone Deacetylase Histone H3 Histones Human Herpesvirus 4 Human Papillomavirus Immune response Immunoblotting Immunoprecipitation In Vitro Individual Interferons Kaposi Sarcoma Knowledge Latent Virus Learning Life Liquid substance Lymphoma Lytic MAPK11 gene MAPK14 gene Malignant Neoplasms Mediating Methods Methylation Modification Molecular Morbidity - disease rate Mouth Diseases Oncogene Proteins Oncogenes Onset of illness Oral Oral Manifestations Oral Medicine Oral cavity Oxidative Stress Oxidative Stress Pathway Papilloma Pathogenesis Patients Periodontal Diseases Periodontal Infection Periodontitis Porphyromonas gingivalis Positioning Attribute Process Regulation Site Specimen Squamous cell carcinoma Streptococcus sanguis Testing Transcript Transplantation Treatment outcome Viral Viral Genes Viral Genome Viral Load result Viral Pathogenesis Virus Work biobank bisulfite burden of illness chromatin modification data integration epigenome epigenomics immunosuppressed improved in vivo inhibitor/antagonist insight microbiome oral bacteria oral cavity epithelium oral pathogen oral wart pathogen promoter public health relevance reactivation from latency response transcriptome sequencing translational approach translational study tumorigenesis virology

项目摘要

DESCRIPTION (provided by applicant): Our increased understanding of the complexity of the microbiome has revealed great potential for pathogenic consequences. The effects of these interactions may be best revealed in further study of the oral cavity. The oral disease burden is exacerbated by activation of opportunistic tumorviruses resulting in oral morbidity and malignancy. Accumulating evidence suggests that epigenetic modifications are at the core of tumorviral pathogenesis modulating 1) host antiviral response and 2) viral reactivation, replication and expression of viral oncoproteins. DNA tumorviruses replicate in oral epithelia and are shed in oral fluids, inferring that replication and reactivation from latency are ongoing. A fundamental question is lack of knowledge regarding the latent to lytic transition in vivo. Why are these viruses so successful in the mouth? We suggest that certain oral bacteria act as environmental triggers that allow for oral epigenetic reprogramming. We now have compelling evidence that oral bacterial products deregulate chromatin modifying enzymes, activate histone marks H3Ac and H4Ac, modify tumorviral promoters, and enhance viral gene expression associated with reactivation and oncogenesis in a species specific manner. Further, these bacterial products diminished the HDAC-associated antiviral interferon response. Collectively, these findings led us to hypothesize that within DNA tumorvirus infected cells, oral bacterial products alter the epigenetic landscape to enhance viral replication and alter cellular innate immune responses in the oral cavity. To test this hypothesis, we will focus on the identification of epigenetic elements central to bacterial modulation of early events in tumorviral pathogenesis. The study goals are to determine: (1) how the common oral pathogen P. gingivalis facilitates viral chromatin modifications critical to reactivation and oncogene expression (SA1 in vitro) (2) modification of host chromatin and gene expression central to the antiviral response (SA2 in vitro) and (3) in vivo correlates of active tumorviral chromatin and concurrent oral bacterial infections (SA3 in vivo). We will employ both standard and modern molecular methods, such as RNA-seq and ChIP-seq, together with targeted inhibition of epigenetic cellular processes to discern the mechanisms of viral chromatin regulation in Pg treated cells. We are uniquely positioned to accomplish these studies at UNC with leading expertise in epigenetics, oral medicine, virology, bacteriology, and computational analysis.

描述（由申请人提供）：我们对微生物组复杂性的日益了解揭示了致病后果的巨大潜力。这些相互作用的影响可能在口腔的进一步研究中得到最好的揭示。机会性肿瘤病毒的激活导致口腔发病和恶性肿瘤，从而加剧了口腔疾病负担。越来越多的证据表明，表观遗传修饰是肿瘤病毒发病机制的核心，调节 1) 宿主抗病毒反应和 2) 病毒再激活、复制和病毒癌蛋白的表达。 DNA肿瘤病毒在口腔上皮细胞中复制，并在口腔液中脱落，这表明复制和潜伏状态的重新激活正在进行中。一个基本问题是缺乏关于体内潜在的裂解转变的知识。为什么是这些病毒在口腔中如此成功？我们认为某些口腔细菌充当环境触发因素，允许口腔表观遗传重编程。我们现在有令人信服的证据表明，口腔细菌产品会解除染色质修饰酶的调节，激活组蛋白标记 H3Ac 和 H4Ac，修饰肿瘤病毒启动子，并以物种特异性方式增强与再激活和肿瘤发生相关的病毒基因表达。此外，这些细菌产物减弱了 HDAC 相关的抗病毒干扰素反应。总的来说，这些发现使我们推测，在 DNA 肿瘤病毒感染的细胞内，口腔细菌产物改变表观遗传景观，从而增强病毒复制并改变口腔中的细胞先天免疫反应。为了检验这一假设，我们将重点鉴定对肿瘤病毒发病机制早期事件的细菌调节至关重要的表观遗传元件。研究目标是确定：(1) 常见口腔病原体牙龈卟啉单胞菌如何促进对重新激活和癌基因表达至关重要的病毒染色质修饰（体外 SA1）(2) 对抗病毒反应至关重要的宿主染色质和基因表达的修饰（SA2）体外）和（3）体内活性肿瘤病毒染色质与并发口腔细菌感染（SA3体内）的相关性。我们将采用标准和现代分子方法，例如 RNA-seq 和 ChIP-seq，以及表观遗传细胞过程的靶向抑制，以辨别 Pg 处理的细胞中病毒染色质调节的机制。我们拥有独特的优势，能够在北卡罗来纳大学完成这些研究，并拥有表观遗传学、口腔医学、病毒学、细菌学和计算分析方面的领先专业知识。