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.

Public Health Relevance

Exposures to environmental toxicants and toxins play a role in the development of many human diseases at least in part by causing epigenetic changes. Understanding the mechanism of initiation and the timing of permanent disease-specific epigenetic changes is important to the development of future prevention and treatment strategies as well as the development of biomarkers of exposure. In this study, we will use a mouse model of toxigenic bacteria-induced tumorigenesis to determine how toxin exposure initiates epigenetic changes and the molecular progression of these changes during tumor formation.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-LWJ-D (TG))
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Tyson, Frederick L
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Indiana University-Purdue University at Indianapolis
Other Basic Sciences
Schools of Medicine
United States
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Vaz, Michelle; Hwang, Stephen Y; Kagiampakis, Ioannis et al. (2017) Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Cancer Cell 32:360-376.e6
Maiuri, Ashley R; Peng, Michael; Sriramkumar, Shruthi et al. (2017) Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis. Cancer Res 77:3467-3478
DeStefano Shields, Christina E; Van Meerbeke, Sara W; Housseau, Franck et al. (2016) Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment. J Infect Dis 214:122-9
Ding, Ning; Bonham, Emily M; Hannon, Brooke E et al. (2016) Mismatch repair proteins recruit DNA methyltransferase 1 to sites of oxidative DNA damage. J Mol Cell Biol 8:244-54
O'Hagan, Heather M (2014) Chromatin modifications during repair of environmental exposure-induced DNA damage: a potential mechanism for stable epigenetic alterations. Environ Mol Mutagen 55:278-91