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

• 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
• 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

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了解增加，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加剧了口腔疾病负担，导致口腔发病率和恶性肿瘤。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）病毒再活化，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，推断复制和潜伏期的再激活正在进行中。一个基本问题是缺乏关于体内潜伏性到溶解性转变的知识。为什么 这些病毒在口腔中如此成功？我们认为，某些口腔细菌作为环境触发器，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，口腔细菌产品去调节染色质修饰酶，激活组蛋白标记H3 Ac和H4 Ac，修改肿瘤病毒启动子，并增强病毒基因表达与重新激活和肿瘤发生在一个物种特异性的方式。此外，这些细菌产物减弱了HDAC相关的抗病毒干扰素应答。总的来说，这些发现使我们假设，在DNA肿瘤病毒感染的细胞内，口腔细菌产物改变了表观遗传景观，以增强病毒复制并改变口腔中的细胞先天免疫反应。为了验证这一假设，我们将集中在鉴定肿瘤病毒发病机制中细菌调节早期事件的表观遗传因素。研究目的是确定：（1）常见口腔病原体牙龈卟啉单胞菌如何促进对再激活和癌基因表达至关重要的病毒染色质修饰（体外SA 1）;（2）宿主染色质修饰和对抗病毒反应至关重要的基因表达（体外SA 2）;（3）活性肿瘤病毒染色质和并发口腔细菌感染的体内相关性（体内SA 3）。我们将采用标准和现代分子方法，如RNA-seq和ChIP-seq，以及对表观遗传细胞过程的靶向抑制，以辨别Pg处理细胞中病毒染色质调控的机制。我们具有独特的优势，能够在生物医学中心完成这些研究，并在表观遗传学、口腔医学、病毒学、细菌学和计算分析方面拥有领先的专业知识。