Dietary Polyphenols Are Consequential Epigenetic Modulators of Gene Expression

描述（由申请人提供）： DNA甲基化是一种重要的表观遗传学机制，它调控着一系列重要的生物学过程。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节作用的研究兴趣激增。本申请的总体目标旨在提供系统的实验证据以建立广泛的新概念，即许多儿茶酚和非儿茶酚多酚（例如，儿茶素、儿茶素/多酚、咖啡多酚）构成了体内DNA甲基化的主要一类高效和重要的调节剂。这一假说是基于大量的初步数据提出的，这些数据表明，膳食多酚化合物可以有效地调节体外和培养细胞中的DNA甲基化状态。为实现这一目标，本研究拟从四个方面展开：1）测定不同膳食多酚对人DNMT的体外抑制作用，并研究其抑制DNMT的动力学机制; 2）进行分子建模研究以确定活性膳食多酚抑制人DNMT的精确分子机制，3）研究膳食多酚对体外培养的人癌细胞和裸鼠移植瘤细胞DNA甲基化和基因表达的影响;和4）研究膳食多酚对培养的小鼠胚胎细胞和完整动物模型中的DNA甲基化、基因再活化以及表观遗传学控制的表型的影响。预计拟议研究的结果将在不久的将来具有直接的临床效用，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.