Novel Methodology for Quantitative High-throughput Cancer Epigenetics

描述（由申请人提供） 摘要：在基因序列没有改变的情况下发生的基因表达的遗传性变化被称为“表观遗传”，这种表观遗传信号传导失调是几种人类生物学过程和癌症等疾病的基础。表观遗传机制的核心是关键的染色质调控网络，如DNA甲基化和组蛋白翻译后修饰（PTM）。组蛋白PTM与基因激活和沉默都有联系，这取决于特定的单个修饰位点。然而，同时发生的组蛋白修饰（组蛋白编码）的不同组合对细胞事件的影响类型知之甚少。这种知识缺乏的主要原因是不存在通过任何生物学手段定量表征或甚至定性鉴定组合组蛋白编码的稳健的高通量方法。我们的工作已经解决了这一不足，开发了一种新的质谱为基础的蛋白质组学平台的定量分子水平的描述组合组蛋白编码信号。我们的初步数据显示，在整个人类基因组中存在数百种不同的组蛋白编码，我们计划应用这种方法来发现动态组蛋白编码如何影响几种类型癌症的基因表达。我们将努力实现在疾病状态期间获取基因组的任何定义部分并准确定量组蛋白编码的目标，检测任何非组蛋白蛋白，然后将其映射回特定的基因组位置，从而在癌症进展期间拍摄染色质景观的快照。目前认识到癌症是遗传和表观遗传转化的疾病。虽然遗传原因与几种类型的癌症有关，但与组蛋白修饰相关的表观遗传方面仍然难以捉摸。我们相信，在这些过程中，在组蛋白密码水平上理解这些改变的组蛋白PTM机制可能会导致增强诊断或开发有益于人类健康的表观遗传疗法。 公共卫生相关性：组蛋白修饰的异常变化与癌症等疾病有关，但目前在组合多位点水平上检测这些变化的技术受到严重限制。我们计划使用新技术来解决这个问题，以发现与几种类型癌症的疾病进展相关的组蛋白修饰模式，从而创造可能有利于疾病诊断或治疗的初步知识。

DESCRIPTION (Provided by the applicant) Abstract: Heritable changes in gene expression occurring without alterations in gene sequence are referred to as "epigenetic", and dysregulation of this epigenetic signaling underlies several human biological processes and diseases such as cancer. At the center of epigenetic mechanisms are critical chromatin regulatory networks such as DNA methylation and histone post-translational modifications (PTMs). Histone PTMs have been linked to both gene activation and silencing depending on the specific single modification site. Nevertheless, what type of effect distinct combinations of simultaneously occurring histone modifications (Histone Codes) have upon cellular events is poorly understood. The main reason for this lack of knowledge is that robust high- throughput methods for quantitative characterization or even qualitative identification of combinatorial Histone Codes by any biological means do not exist. Our work has addressed this deficiency by developing a novel mass spectrometry based proteomic platform for quantitative molecular level descriptions of combinatorial Histone Code signaling. Our preliminary data reveal that hundreds of distinct Histone Codes exist throughout the human genome, and we plan to apply this approach to discover how dynamic Histone Codes influence gene expression in several types of cancers. We will work towards the goal of taking any defined part of the genome during disease state and accurately quantifying the Histone Codes, detecting any non-histone proteins, and then mapping these back to the specific genomic locations, thereby taking a snapshot of the chromatin landscape during cancer progression. It is currently appreciated that cancer is a disease of both genetic and epigenetic transformations. While genetic causes have been associated with several types of cancers, epigenetic aspects related to histone modifications remain elusive. We believe that comprehension of these altered histone PTM mechanisms at the Histone Code level in these processes may lead to enhanced diagnostics or development of epigenetic therapy beneficial for human health. Public Health Relevance: Aberrant changes in histone modifications have been linked to diseases such as cancer, but currently the technology to detect these changes on a combinatorial multisite level is severely limited. We plan to use novel technology to address this problem to discover histone modification patterns associated with disease progression in several types of cancers, thereby creating initial knowledge that may be beneficial for disease diagnostics or treatment.