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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

基本信息

批准号：
8306316
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
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-21 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306316
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 public health relevance

项目摘要

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. PUBLIC HEALTH RELEVANCE: The expression of the human papillomavirus (HPV) E6 and E7 oncoproteins is necessary for the induction and maintenance of the transformed state, which makes cervical cancer a unique model to study human cancer development. Therefore, cervical cancer provides a well-defined system of cancer development to study the regulation of polycomb group proteins and histone demethylases and the functional consequences of their deregulation in cancer. A detailed mechanistic understanding of epigenetic changes that occur during cervical cancer development, specifically those directly caused by HPV oncoproteins, will provide critical insights into the development of human solid tumors.

描述(申请人提供)：癌症历来被认为是导致癌基因激活和/或肿瘤抑制基因失活的突变的结果。然而，自从1983年的第一份报告描述了癌症中DNA甲基化模式的改变以来，很明显，表观遗传改变、DNA甲基化模式的改变和组蛋白修饰对人类癌症的发生有重要贡献。表观遗传异常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后果。因此，癌症既是一种遗传病，也是一种表观遗传病。与基因突变的不可逆转性质形成鲜明对比的是，表观遗传异常可能是可逆的，因此允许进行治疗干预。这项职业发展提案的总体目标是帮助麦克劳克林-德鲁宾博士在癌症表观遗传学研究方面建立独立的学术生涯，特别是在HPV颠覆宿主表观遗传学计划的研究方面。培训环境是在共同导师的实验室里进行的，他们是布里格姆妇女医院/哈佛医学院的Karl M|nger博士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上。候选人的初步数据显示，组蛋白H3裂解27三甲基化(H3K27me3)，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E2F6-PcG抑制复合体，在表达HPV16E7的细胞中减少。此外，候选人还发现，HPV16E7诱导了移除这种抑制性组蛋白修饰的酶，组蛋白去甲基酶UTX和JMJD3。此外，在表达HPV16E7的细胞中，一组UTX和JMJD3应答的HOX基因的表达水平显著升高，而E7介导的JMJD3过表达是p16INK4A表达的关键。这项研究的第一个目的是确定HPVE7诱导表观遗传重编程的机制。第二个目标集中在表观遗传重新编程的生物学终点，包括在癌症发生中的潜在作用。公共卫生相关性：人类乳头瘤病毒(HPV)E6和E7癌蛋白的表达是诱导和维持转化状态所必需的，这使宫颈癌成为研究人类癌症发展的独特模型。因此，宫颈癌为研究多梳状蛋白和组蛋白去甲基酶的调控及其去调控在癌症中的功能后果提供了一个明确的癌症发展系统。对宫颈癌发展过程中发生的表观遗传学变化，特别是那些由HPV癌蛋白直接引起的表观遗传学变化的详细机制的理解，将为人类实体肿瘤的发展提供关键的见解。