Epigenetic Reprogramming by the Human Papillomavirus E7 Oncoprotein

描述（由申请人提供）：癌症历来被视为导致致癌基因激活和/或肿瘤抑制基因失活的突变的结果。然而，自1983年首次报道癌症中DNA甲基化模式的改变以来，表观遗传改变（DNA甲基化模式的改变和组蛋白修饰）对人类癌变起重要作用已经变得很清楚。表观遗传畸变导致染色质结构和基因表达的遗传变化，其功能后果类似于基因突变引起的变化。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形成鲜明对比的是，表观遗传畸变具有潜在的可逆性，因此可以进行治疗干预。本职业发展计划的总体目标是协助McLaughlin-Drubin博士在癌症表观遗传学研究，特别是HPV对宿主表观遗传学程序的颠覆方面建立独立的学术生涯。培训环境是在共同导师，布里格姆妇女医院/哈佛医学院的Karl M bbbbinger博士和哈佛医学院的杨石博士的实验室中进行的。本研究旨在阐明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（H3K27me3），一种沉默染色质的表观遗传修饰，以及通常与沉默染色质结合的E2F6-PcG抑制复合物，在表达HPV16 E7的细胞中减少。此外，候选人发现hpv16e7诱导去除这种抑制性组蛋白修饰的酶，组蛋白去甲基化酶UTX和JMJD3。此外，UTX-和JMJD3应答的HOX基因子集在HPV16 E7表达细胞中表达水平显著升高，E7介导的JMJD3过表达对p16INK4A表达至关重要。提出的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。第二个目标侧重于这种表观遗传重编程的生物学终点，包括致癌的潜在作用。

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.