Epigenetic effects of chronic alcohol consumption on colonic mucosa

描述（申请人提供）：流行病学研究表明，饮酒会增强结直肠癌的发生，特别是在叶酸耗竭和/或亚甲基四氢叶酸还原酶（MTHFR）纯合变异基因型的个体中，这表明酒精的共致癌作用是通过叶酸介导的一碳代谢传递的，并提倡酒精与MTHFR基因之间的相互作用，其维持生物甲基化和核苷酸合成之间的平衡。最近，我们确定了这样一个事实，即慢性酒精消费诱导高同型半胱氨酸血症和基因组DNA低甲基化在啮齿动物结肠，表明酒精对一碳代谢和表观遗传现象的有效影响，并随后贷款，慢性酒精消费修改关键基因表达通过表观遗传变化，并提供了一个共同致癌的环境在结肠粘膜。我们的长期目标是找到化学预防酒精相关癌症的有效策略。本提案中概述的研究旨在确定饮酒影响结直肠癌发生的表观遗传机制。因此，我们假设长期饮酒会干扰结肠中的一碳代谢，从而改变表观遗传现象，包括DNA甲基化和组蛋白甲基化以及关键基因表达。我们进一步假设，改变一碳代谢平衡的条件，如叶酸消耗，衰老和MTHFR， 多态性，加剧这些表观遗传现象引起的慢性饮酒。这一应用是创新的，因为两种提出的表观遗传现象，组蛋白甲基化和启动子DNA甲基化，从未被探索用于关于酒精相关致癌作用的研究，并且所提出的酒精和MTHFR基因之间的表观遗传相互作用是一个新概念，使得能够通过基因型和营养状态进行个体定制的化学预防。基于这项申请的结果，我们将申请一项研究项目资助，以最终确定长期饮酒对结直肠癌发生的表观遗传作用。如果这些研究能够精确地定义酒精相关致癌的表观遗传机制，我们就可以为这些癌症开发一种新的化学预防策略。

DESCRIPTION (provided by applicant): Epidemiologic studies have demonstrated that alcohol consumption enhances colorectal carcinogenesis especially in individuals with folate depletion and/or methylenetetrahydrofolate reductase (MTHFR) homozygous variant genotype, indicating that the co-carcinogenic effect of alcohol is conveyed through the folate mediated one-carbon metabolism, as well as advocating an interaction between alcohol and MTHFR gene, which maintains a balance between biological methylation and nucleotide synthesis. Recently, we identified the fact that chronic alcohol consumption induces hyperhomocysteinemia and genomic DNA hypomethylation in the rodent colon, indicating the potent effects that alcohol exerts on onecarbon metabolism and epigenetic phenomena, and subsequently lending that chronic alcohol consumption modifies critical gene expression through epigenetic changes and provides a co-carcinogenic milieu in the colonic mucosa. Our long-term goal is to find effective strategies for the chemoprevention of alcohol-associated cancer. The studies outlined in this proposal are aimed at defining epigenetic mechanisms by which alcohol consumption affects colorectal carcinogenesis. We therefore hypothesize that chronic alcohol consumption disturbs one-carbon metabolism in the colon and thereby alters epigenetic phenomena including DNA methylation and histone methylation as well as critical gene expression. We further hypothesized that conditions which alter the balance of one-carbon metabolism, such as folate depletion, aging and MTHFR polymorphism, aggravate these epigenetic phenomena induced by chronic alcohol consumption. This application is innovative because two proposed epigenetic phenomena, histone methylation and promoter DNA methylation, have never been explored for the study regarding the alcohol-associated carcinogenesis and the proposed epigenetic interaction between alcohol and MTHFR gene is a new concept that enables individually tailored chemoprevention by genotypes and nutrition status. Based on the results of this application we will apply for a research project grant to finalize the epigenetic effect of chronic alcohol consumption on colorectal carcinogenesis. If those studies can precisely define the epigenetic mechanism for alcohol-associated carcinogenesis, we can develop a new chemopreventive strategy for those cancers.