Dietary Polyphenols Are Consequential Epigenetic Modulators of Gene Expression

膳食多酚是基因表达的重要表观遗传调节剂

• 批准号: 7434725
• 负责人: BAO-TING ZHU
• 金额: $ 36万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434725
• 关键词: DNA methylation; catechols; computer simulation; diet; embryo /fetus cell /tissue; enzyme activity; enzyme inhibitors; enzyme mechanism; enzyme structure; epigenetics; flavonoids; food; gene expression; gene induction /repression; intermolecular interaction; laboratory mouse; methyltransferase; molecular dynamics; plastics; tissue /cell culture; xenotransplantation

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.

描述（由申请人提供）： DNA 甲基化代表了一种重要的表观遗传机制，可调节多种重要的生物过程。 DNA 甲基化模式的异常与多种人类疾病有关。近年来，人们对各种生物活性食品成分对 DNA 甲基化、基因沉默和重新激活的潜在调节作用的研究兴趣激增。本申请的总体目标是提供系统的实验证据，以建立一个广泛的新颖概念，即我们日常饮食中大量存在的许多儿茶酚和非儿茶酚多酚（例如茶儿茶素、生物类黄酮/异黄酮类、咖啡多酚）构成了一个主要类别体内 DNA 甲基化的高效且重要的调节剂。这一假设是在大量初步数据的基础上提出的，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。为了实现这些目标，计划制定四个范围广泛但又紧密相连的具体目标：1）确定各种膳食多酚对人类DNMT的体外抑制作用，并研究人类DNMT抑制的动力学机制； 2）开展分子模型研究，确定活性膳食多酚抑制人类DNMT的精确分子机制，并探讨这些膳食化学物质抑制人类DNMT的构效关系； 3) 研究膳食多酚对培养物和裸鼠异种移植物中人类癌细胞DNA甲基化和基因表达的影响； 4) 研究膳食多酚对培养物和完整动物模型中小鼠胚胎细胞 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。