Influences of arsenic and folate on histone methylation marks

 描述(由申请人提供)：全球约有1.4亿人长期暴露在浓度超过世卫组织安全饮用水指南的砷(As)中。砷导致许多不利的健康后果，包括几种类型的癌症。然而，潜在的机制尚不清楚。尽管消除砷暴露仍然是预防砷毒性的主要目标，但随着接触的减少，癌症风险仍然存在几十年。因此，了解AS导致人类疾病(如癌症)的机制，对于制定未来减少AS毒性的干预策略至关重要。虽然AS不会致突变，但越来越多的文献表明，AS会导致表观遗传失调，包括组蛋白甲基化模式的改变。因此，组蛋白甲基化的失调可能是AS致癌的机制之一。目前，人们对接触砷污染饮用水的人群中的组蛋白甲基化知之甚少。重要的是，S-腺苷蛋氨酸为组蛋白甲基化提供了甲基化基团，而S-腺苷同型半胱氨酸是组蛋白甲基化反应的有效产物抑制剂；由于腺苷甲硫氨酸和同型半胱氨酸都受到叶酸依赖的一碳代谢的严格调控，叶酸营养状况也可能通过对组蛋白甲基化的影响而影响组蛋白甲基化。然而，科学文献中缺乏关于砷暴露人群中SAM、SAH、叶酸和组蛋白甲基化之间关系的信息。在这项研究中，[3]组蛋白修饰(H3K36me2，[H3K36me3]，H3K79me2)被选择，因为它们在体外被已知受到AS和/或甲基供体的影响。该项目的第一个目的是检验下列假设：1)随着暴露增加组蛋白标记H3K36me2的全球[和基因特异性]水平，[并导致H3K36me3相应的下降]，来自长期暴露在受砷污染的饮用水中的孟加拉国成年人的外周血单核细胞(PBMC)，2)H3K36me2的全球增加是由组蛋白赖氨酸去甲基酶2B(Kdm2b)mRNA表达的减少所调节的，以及3)H3K36me2[和H3K36me3]的水平即使在通过使用去除砷的滤水器来减少暴露后仍然存在。该项目的第二个目的是检验叶酸营养状况、SAM、SAH和叶酸(FA补充剂)是否会影响在叶酸和肌酸补充试验(FACT)中暴露的孟加拉国成年人的PBMC中H3K36me2、[H3K36me3]和H3K79me2的全球[和基因特异性]水平，这是一项关于FA和/或肌酸补充剂的双盲、随机、安慰剂对照试验。更好地了解As、叶酸和组蛋白甲基化之间的关系将增加我们对As导致人类疾病的机制的了解，并将提高我们设计未来干预策略的能力，例如营养素干预，以防止或扭转表观遗传失调，从而减轻暴露在As污染饮用水中的人群的疾病负担。

 DESCRIPTION (provided by applicant): Worldwide ~140 million people are chronically exposed to arsenic (As) at concentrations that exceed the WHO guideline for safe drinking water. Arsenic causes many adverse health outcomes, including several types of cancer. However, the underlying mechanisms are unknown. Although eliminating As exposure remains the primary goal for preventing As toxicity, cancer risks persist decades after As exposure has been reduced. Therefore, understanding the mechanisms by which As causes human diseases, such as cancer, is critical for developing future intervention strategies to reduce As toxicity. Though As is not mutagenic, an increasing body of literature suggests that As causes epigenetic dysregulation, including altered histone methylation patterns. Thus, dysregulation of histone methylation may be one mechanism by which As causes cancer. Currently, little is known about histone methylation in human populations exposed to As-contaminated drinking water. Importantly, S-adenosylmethionine (SAM) provides the methyl groups for histone methylation, and S-adenosylhomocysteine (SAH) is a potent product inhibitor of SAM-dependent methylation reactions; since SAM and SAH are both tightly regulated by folate-dependent one-carbon metabolism, folate nutritional status may also influence histone methylation through its effects on SAM and SAH. However, there is a lack of information in the scientific literature on relationships between SAM, SAH, folate, and histone methylation in As-exposed populations. For this study, [three] histone modifications (H3K36me2, [H3K36me3], H3K79me2) were selected, because they are known to be influenced by As and/or methyl donors in vitro. The first aim of this project is to test the following hypotheses: 1) As exposure increases global [and gene-specific] levels of histone mark H3K36me2, [and causes a corresponding decrease in H3K36me3], in peripheral blood mononuclear cells (PBMCs) from Bangladeshi adults who are chronically exposed to As- contaminated drinking water, 2) the global increase in H3K36me2 is mediated by a decrease in histone lysine demethylase 2B (KDM2B) mRNA expression, and 3) H3K36me2 [and H3K36me3] levels persist even after As exposure has been reduced through the use of water filters that remove As. The second aim of this project is to test the hypotheses that folate nutritional status, SAM, SAH, and folic acid (FA supplementation, influence global [and gene-specific] levels of H3K36me2, [H3K36me3], and H3K79me2 in PBMCs from As-exposed Bangladeshi adults enrolled in the Folic Acid and Creatine Trial (FACT), which is a double-blind, randomized, placebo-controlled trial of FA and/or creatine supplementation. Better understanding the relationships between As, folate, and histone methylation will increase our knowledge of the mechanisms by which As causes human diseases, and will improve our ability to design future intervention strategies, such as nutritiona interventions, to prevent or reverse epigenetic dysregulation and thereby reduce disease burden in populations exposed to As-contaminated drinking water.