Dietary Polyphenols Are Consequential Epigenetic Modulators of Gene Expression

描述(由申请人提供)： DNA甲基化代表着一种重要的表观遗传机制，它调节着一系列重要的生物过程。DNA甲基化模式的异常与各种人类疾病有关。近年来，人们对各种生物活性食品成分对DNA甲基化、基因沉默和再激活的潜在调控作用的研究兴趣激增。这项应用的总体目标是提供系统的实验证据，以建立一个广泛的新概念，即在我们的日常饮食中大量存在的许多儿茶素和非儿茶多酚(例如，茶儿茶素、生物类黄酮/异黄酮类、咖啡多酚)构成了体内DNA甲基化的一大类高效和相应的调节剂。这一假说是基于大量的初步数据提出的，这些数据表明，饮食中的多酚化合物在体外和培养细胞中都能有效地调节DNA甲基化状态。为了实现这一目标，计划有四个范围广泛但紧密交错的特定目标：1)确定不同饮食多酚对人DNMT的体外抑制作用，并研究其抑制人DNMT的动力学机制；2)进行分子模拟研究，以确定活性饮食多酚抑制人DNMT的确切分子机制，并探讨这些饮食化学物质对人DNMT抑制的构效关系；3)研究饮食多酚对培养的人癌细胞和裸鼠移植瘤DNA甲基化和基因表达的影响；4)研究饮食多酚对小鼠胚胎细胞DNA甲基化、基因再激活以及表观遗传控制表型的影响。预计拟议研究的结果在不久的将来将直接应用于临床，并对人类健康产生深远的影响。

DESCRIPTION (provided by applicant): DNA methylation represents an important epigenetic mechanism that regulates a wide array of important biological processes. Abnormality in DNA methylation patterns is associated with various human disease conditions. In recent years, there has been a surge in research interest to address the potential modulating effect of various bioactive food components on DNA methylation, gene silencing, and reactivation. The overall objective of this application is aimed at providing systematic experimental evidence to establish a broad novel concept that many of the catecholic and noncatecholic polyphenols (e.g., tea catechins, bioflavonoids/isoflavonoids, coffee polyphenols) abundantly present in our daily diet constitute a major class of highly effective and consequential modulators of DNA methylation in vivo. This hypothesis is proposed on the basis of extensive preliminary data showing that dietary polyphenolic compounds can effectively modulate DNA methylation status in vitro and also in cultured cells. To achieve the goals, four broad-scoped but tightly-interlaced specific aims are planned to: 1) Determine in vitro inhibition of human DNMTs by various dietary polyphenols, and also study the kinetic mechanisms of human DNMT inhibition; 2) Conduct molecular modeling studies to determine the precise molecular mechanisms of human DNMT inhibition by active dietary polyphenols, and also to probe the structure-activity relationship of human DNMT inhibition by these dietary chemicals; 3) Study the effect of dietary polyphenols on DNA methylation and gene expression in human cancer cells grown in culture and in nude mice as xenografts; and 4) Study the effect of dietary polyphenols on DNA methylation, gene reactivation, and also on epigenetically-controlled phenotypes in mouse embryonic cells in culture and also in an intact animal model. It is expected that the outcomes of the proposed studies will have direct clinical utility in the near future and far-reaching human health implications.