Epigenetic Reprogramming by the Human Papillomavirus E7 Oncoprotein

人乳头瘤病毒 E7 癌蛋白的表观遗传重编程

• 批准号: 8145702
• 负责人: Margaret Erin McLaughlin-Drubin
• 金额: $ 14.04万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145702
• 关键词: Address; Applications Grants; Binding; Biological; Biological Markers; CDKN2A gene; Cells; Chromatin; Chromatin Structure; Complex; Cyclin-Dependent Kinase Inhibitor 2A; DNA Methylation; Data; Development; Disease; Environment; Enzymes; Epigenetic Process; Epithelial Cells; Gene Expression; Gene Mutation; Genomics; Goals; HPV-High Risk; Hereditary Disease; Histone H3; Histones; Homeobox Genes; Hospitals; Human; Human Development; Human Papillomavirus; Human papillomavirus 16; Laboratories; Lead; Lesion; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Maps; Mediating; Mentors; Modeling; Modification; Mutation; Nature; Oncogene Activation; Oncogene Proteins; Oncogenic; Pattern; Play; Polycomb; Premalignant; Preparation; Process; Proteins; Proteomics; Regulation; Regulatory Element; Reporting; Research; Research Project Grants; Role; Solid Neoplasm; Stress; System; Testing; Therapeutic Intervention; Training; Tumor Suppressor Proteins; Tumor-Suppressor Gene Inactivation; Up-Regulation; Ursidae Family; Woman; Yang; carcinogenesis; career; career development; histone modification; human papilloma virus oncogene; imprint; inhibitor/antagonist; insight; medical schools; programs; promoter; protein complex

DESCRIPTION (provided by applicant): Cancer has historically been viewed as a result of mutations that lead to the activation of oncogenes and/or the inactivation of tumor suppressor genes. However, since the initial report in 1983 describing an altered DNA methylation pattern in cancer, it has become clear that epigenetic alterations, changes in patterns of DNA methylation and histone modifications, importantly contribute to human carcinogenesis. Epigenetic aberrations result in heritable changes in chromatin structure and gene expression with functional consequences akin to those induced by genetic mutations. Hence, cancer is as much an epigenetic disease as it is a genetic disease. In stark contrast to the irreversible nature of genetic mutations, epigenetic aberrations are potentially reversible, thus allowing for therapeutic intervention. The overall goal of this career development proposal is to assist in establishing the independent academic career of Dr. McLaughlin-Drubin in the study of cancer epigenetics and specifically of HPV subversion of host epigenetic programs. The training environments are in the laboratories of the co-mentors, Dr. Karl M|nger at Brigham and Women's Hospital/Harvard Medical School and Dr. Yang Shi at Harvard Medical School. The specific aims of the proposed research project focus on elucidating the mechanism of HPV E7 epigenetic reprogramming. The candidate's preliminary data has shown that histone H3 lysine27 trimethylation (H3K27me3), an epigenetic modification that silences chromatin, as well as E2F6-PcG repressor complexes that normally bind to silenced chromatin, are decreased in HPV16 E7 expressing cells. In addition, the candidate discovered that HPV16 E7 induces the enzymes that remove this repressive histone modification, the histone demethylases UTX and JMJD3. Moreover, a subset of UTX- and JMJD3-responsive HOX genes are expressed at markedly higher levels in HPV16 E7 expressing cells, and E7 mediated JMJD3 over- expression is critical for p16INK4A expression. The first aim of the proposed research is to determine the mechanism of HPV E7 induced epigenetic reprogramming. The second aim focuses on biological endpoints of this epigenetic reprogramming, including the potential role in carcinogenesis.

描述（由申请人提供）：癌症历来被视为导致癌基因激活和/或肿瘤抑制基因失活的突变的结果。然而，自从1983年描述癌症中改变的DNA甲基化模式的最初报告以来，已经清楚的是，表观遗传学改变，DNA甲基化和组蛋白修饰模式的变化，对人类致癌作用有重要贡献。表观遗传畸变导致染色质结构和基因表达的可遗传变化，其功能后果类似于基因突变引起的功能后果。因此，癌症既是一种遗传疾病，也是一种表观遗传疾病。与基因突变的不可逆性质形成鲜明对比的是，表观遗传畸变是潜在可逆的，从而允许治疗干预。该职业发展计划的总体目标是协助建立McLaughlin-Drubin博士在癌症表观遗传学研究中的独立学术生涯，特别是HPV对宿主表观遗传学计划的颠覆。培训环境是在共同导师的实验室里，|布里格姆妇女医院/哈佛医学院的恩格尔和哈佛医学院的杨石博士。拟议研究项目的具体目标集中在阐明HPV E7表观遗传重编程的机制。候选人的初步数据表明，组蛋白H3赖氨酸27三甲基化（H3 K27 me 3）（一种使染色质沉默的表观遗传修饰）以及通常与沉默的染色质结合的E2 F6-PcG阻遏复合物在HPV 16 E7表达细胞中减少。此外，该候选人发现HPV 16 E7诱导去除这种抑制性组蛋白修饰的酶，即组蛋白脱甲基酶UTX和JMJD 3。此外，UTX和JMJD 3应答性HOX基因的子集在表达HPV 16 E7的细胞中以显著更高的水平表达，并且E7介导的JMJD 3过表达对于p16 INK 4A表达是关键的。这项研究的第一个目的是确定HPV E7诱导表观遗传重编程的机制。第二个目标集中在这种表观遗传重编程的生物学终点，包括在致癌作用中的潜在作用。