A Blueprint for Oncogenic Epigenetic Reprogramming

致癌表观遗传重编程的蓝图

• 批准号: 7853988
• 负责人: Siavash Kurdistani
• 金额: $ 231万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853988
• 关键词: Aberrant DNA Methylation; Adenoviruses; Antiviral Response; Binding; Biological Assay; Biology; Cancer Biology; Cancer cell line; Cancerous; Cell Proliferation; Cells; Defense Mechanisms; Development; Diagnostic; Enzymes; Epigenetic Process; Event; Furniture; Genes; Genetic; Genome; Hereditary Disease; Housing; Human; Infection; Lead; Learning; Malignant Neoplasms; Measurement; Mediating; Modeling; Molecular; Neoplastic Cell Transformation; Normal Cell; Oncogene Proteins; Oncogenic; Papillomavirus; Pathway interactions; Pattern; Phenotype; Process; Protein p53; Proteins; Regulation; Regulator Genes; Retinoblastoma; Series; Therapeutic; Time; Viral; Virus; Work; abstracting; cancer cell; cell growth; design; histone modification; human disease; insight; malignant state; meetings; metaplastic cell transformation; prognostic; programs; public health relevance; tumor initiation

DESCRIPTION (Provided by the applicant) Abstract: While cancer is a genetic disease, the cancerous cellular state is associated with multiple epigenetic alterations including aberrant DNA methylation and histone modification patterns. A significant challenge in cancer biology is to elucidate the precise order of epigenetic alterations during tumor initiation and progression and their contributions to the transformed phenotype. To meet this challenge, one requires a model of cellular transformation that is temporally traceable from a normal to a malignant state. Cancer cell lines are not necessarily good models as they have already accumulated hundreds to thousands of genetic and epigenetic alterations. Here I propose to study the oncogenic transformation of normal human cells by viral oncoproteins as a model to determine the precise epigenetic reprogramming events occurring along the path of neoplastic transformation. Viral oncoproteins such as the Adenovirus small e1a or Papilloma virus E7 have been extraordinarily useful in delineating the central molecular players that regulate cell proliferation such as the retinoblastoma (RB) and p53 tumor suppressors. Our work has recently elucidated a defined global epigenetic reprogramming by one viral oncoprotein, e1a, that forces normal cells to escape quiescence-a hallmark of cancer. Importantly, e1a directly implements a precise and coordinated mechanism of regulation of thousands of host cell genes leading to cellular transformation by interacting and rearranging specific epigenetic modifiers across the whole genome in a time-dependent manner. This provides a powerful model that is amenable to time-series measurements with phenotypically defined endpoints, enabling one to delineate the successive order of epigenetic alterations that contribute to oncogenic transformation. By understanding how e1a orchestrates a specific sequence of epigenetic alterations for cellular transformation, we should learn greatly about the functions and mechanisms of fundamental epigenetic processes in normal biology and human disease, especially cancer. Public Health Relevance: Cancer cells depend on multiple alterations in various molecular pathways to overcome normal defense mechanisms against uncontrolled cell replication. However, how these changes cooperate in time to transform a normal cell to a cancerous one is not very well understood. Certain viruses encode proteins, such as the Adenovirus e1a, that can force a normal cell to overcome its defense mechanism and to replicate-a hallmark of cancer-so that more viral progenies are produced. Because viruses use the cell's own machinery, they have been extraordinarily revealing about processes that must be altered for cancer to arise. We have discovered that the e1a protein displays a highly coordinated program of binding to different sets of host genes at different times after infection. Through such temporally-ordered pattern of binding, the e1a protein rearranges a specific set of gene regulatory enzymes so as to promote cell growth and replication and to repress antiviral responses and molecular pathways that would normally stop the cell from dividing. This is akin to rearranging the furniture in the host's house to serve the guest's sinister purposes. This proposal aims to use e1a-mediated cellular transformation to generate a blueprint for the successive order of events that must occur in a precise manner for cancer to develop. This work may provide fundamental insights into the initial molecular events that lead to cancer development, enabling us to design better therapeutics and/or develop diagnostic and prognostic assays that may aid in personalization of therapy.

描述（由申请人提供） 摘要：虽然癌症是一种遗传性疾病，但癌性细胞状态与多种表观遗传改变相关，包括异常 DNA 甲基化和组蛋白修饰模式。癌症生物学的一个重大挑战是阐明肿瘤发生和进展过程中表观遗传改变的精确顺序及其对转化表型的贡献。为了应对这一挑战，人们需要一种可以在时间上追踪从正常状态到恶性状态的细胞转化模型。癌细胞系不一定是好的模型，因为它们已经积累了数百到数千个遗传和表观遗传改变。在这里，我建议研究病毒癌蛋白对正常人类细胞的致癌转化作为模型，以确定沿着肿瘤转化路径发生的精确表观遗传重编程事件。腺病毒小 e1a 或乳头瘤病毒 E7 等病毒癌蛋白在描述视网膜母细胞瘤 (RB) 和 p53 肿瘤抑制因子等调节细胞增殖的核心分子参与者方面非常有用。我们的工作最近阐明了一种由一种病毒癌蛋白 e1a 引起的明确的全局表观遗传重编程，它迫使正常细胞逃避静止——这是癌症的一个标志。重要的是，e1a 直接实现了数千个宿主细胞基因的精确协调调节机制，通过以时间依赖的方式在整个基因组中相互作用和重新排列特定的表观遗传修饰剂，从而导致细胞转化。这提供了一个强大的模型，适用于具有表型定义终点的时间序列测量，使人们能够描绘有助于致癌转化的表观遗传改变的连续顺序。通过了解 e1a 如何协调细胞转化的特定表观遗传改变序列，我们应该深入了解正常生物学和人类疾病（尤其是癌症）中基本表观遗传过程的功能和机制。 公共健康相关性：癌细胞依赖于各种分子途径的多种改变来克服针对不受控制的细胞复制的正常防御机制。然而，这些变化如何及时配合将正常细胞转变为癌细胞尚不清楚。某些病毒编码蛋白质，例如腺病毒 e1a，可以迫使正常细胞克服其防御机制并进行复制（这是癌症的标志），从而产生更多的病毒后代。由于病毒使用细胞自身的机制，因此它们非常揭示了癌症发生必须改变的过程。我们发现，e1a 蛋白表现出高度协调的程序，在感染后的不同时间与不同组的宿主基因结合。通过这种按时间顺序排列的结合模式，e1a 蛋白重新排列一组特定的基因调节酶，以促进细胞生长和复制，并抑制通常会阻止细胞分裂的抗病毒反应和分子途径。这类似于重新布置主人家里的家具来满足客人的险恶目的。该提案旨在利用 e1a 介导的细胞转化为癌症发展必须以精确方式发生的事件的连续顺序生成蓝图。这项工作可能为导致癌症发展的初始分子事件提供基本见解，使我们能够设计更好的治疗方法和/或开发可能有助于个性化治疗的诊断和预后测定。