Toxin-Associated Oxidative DNA Damage Initiates Tumor-Specific Epigenetic Changes

描述(由申请人提供)：在这个项目中，目的是了解暴露在环境毒素中导致疾病特异性表观遗传学变化的机制。虽然对毒物和毒素暴露的表观遗传变化已经进行了研究，但这些研究中的大多数都检查了DNA甲基化的变化，这被认为是后来更永久性的表观遗传变化。在与毒素暴露有关的肿瘤发生过程中，异常的DNA超甲基化会沉默肿瘤抑制基因的表达。具体了解从急性暴露到疾病形成的表观遗传变化的启动、时间和分子进展将使我们能够为环境暴露引起的疾病制定更好的预防和治疗策略。我们已经在体外证明了暴露在氧化损伤下会导致表观遗传沉默蛋白染色质结合的全基因组急性变化，这表明了一种可能启动表观遗传变化的机制。在这里，我们使用接触产毒细菌，肠毒素脆弱类杆菌(ETBF)，已知与人类的急性和慢性结肠炎和结肠癌有关，以诱导结肠炎，随后在小鼠模型中发生肿瘤。因此，了解这些细菌引起的表观遗传变化背后的机制将与人类疾病相关。此外，由于像许多毒物和其他毒素一样，暴露在ETBF中会导致炎症和相关的氧化损伤增加，我们模型的发现可以转化为许多不同的暴露，导致人类疾病。这项应用的目标是了解毒素暴露如何启动疾病特有的表观遗传变化，包括这种变化的时间和分子进展。利用ETBF感染，我们将确定急性毒素暴露是否导致表观遗传沉默蛋白染色质结合的全基因组变化，以及这种结合变化是否依赖于氧化DNA损伤。此外，利用炎症诱导肿瘤发生的ETBF模型，我们将研究这些急性表观遗传学变化是否导致疾病特异性的表观遗传学变化，以及从特定基因启动子上的表观遗传沉默蛋白的丰富到这些启动子的DNA甲基化的分子进展。

DESCRIPTION (provided by applicant): In this project, the intent is to understand the mechanism by which exposure to an environmental toxin causes disease-specific epigenetic changes. While epigenetic changes in response to toxicant and toxin exposure have been studied, the majority of these studies have examined changes in DNA methylation, which is thought to be a later more permanent epigenetic change. During tumorigenesis, which has been linked to toxin exposure, aberrant DNA hypermethylation silences the expression of tumor suppressor genes. Specifically understanding the initiation, timing, and molecular progression of epigenetic changes from acute exposure to disease formation will allow us to develop better prevention and treatment strategies for diseases caused by environmental exposure. We have demonstrated in vitro that exposure to oxidative damage causes acute genome-wide changes in the chromatin binding of epigenetic silencing proteins, suggesting a mechanism by which epigenetic changes may be initiated. Here we use exposure to toxigenic bacteria, enterotoxigenic Bacteroides fragilis (ETBF), which is known to be associated with acute and chronic colitis and colon cancer in humans, to induce colon inflammation followed by tumorigenesis in a mouse model. Therefore, understanding the mechanism behind epigenetic changes induced by these bacteria will be relevant to human disease. Furthermore, because like many toxicants and other toxins, exposure to ETBF causes an increase in inflammation and associated oxidative damage, the findings from our model can be translated to many different exposures that cause human disease. The goal of this application is to understand how toxin exposure initiates disease-specific epigenetic changes, including the timing and molecular progression of such changes. Using ETBF infection, we will determine if acute toxin exposure results in genome-wide changes in the chromatin binding of epigenetic silencing proteins and if this change in binding is dependent on oxidative DNA damage. Furthermore, using the ETBF model of inflammation-induced tumorigenesis we will investigate if these acute epigenetic changes result in disease-specific epigenetic changes as well as study the molecular progression from the enrichment of epigenetic silencing proteins at specific gene promoters to DNA methylation of those promoters.