Cytosine methylation (5-methylcytosine (MeC)) regulates gene expression in a tissue-specific manner. These methylation marks are introduced by DNA methyltransferases (DNMTs), which catalyze de novo methylation of CpG sites and maintain DNA methylation patterns to allow for activation and silencing of specific genes. Ten eleven translocation proteins (Tet) catalyze ?-ketoglutarate-dependent oxidation of MeC to 5-hydroxymethyl- cytosine (hmC), 5-formylcytosine (fC), and 5-carboxylcytosine (caC). These oxidized forms of MeC serve as demethylation intermediates, leading to gene reactivation. Furthermore, studies in the brain and embryonic stem cells have shown that hmC, fC, and caC can be recognized by specific protein readers and may have epigenetic functions of their own. Cytosine methylation patterns are stable in normal somatic tissues, but are significantly altered in many diseases including cancer, asthma, and autism. Specifically, scrambled DNA methylation and hydroxymethylation in cancer leads to silencing of tumor suppressor genes and activation of protooncogenes. We have shown that chronic inflammation and exposure to tobacco nitrosamines induces early epigenetic changes in the A/J model of lung cancer. These alterations are detectable long before the formation of tumors and include changes in cytosine methylation, hydroxymethylation, formylation, and histone acetylation. However, the functional outcomes of these epigenetic changes remain to be determined. This research plan focuses on investigating the functions of MeC, hmC, fC, and caC in the lung, characterizing epigenetic changes associated with smoking and inflammation, and elucidating the epigenetic functions of Tet proteins in the lung. Taken together, these studies will contribute to our understanding of normal epigenetic mechanisms in the lung and their response to smoking and inflammation.
This application will investigate the effects of cigarette smoke and smoking-associated inflammation on the dynamics of DNA methylation and demethylation in the lung and elucidate the mechanisms by which gene expression patterns can be affected in smokers and individuals exposed to second hand smoke. These studies will improve our understanding of the fundamental mechanisms of lung cancer and help the development of new prevention and treatment strategies.
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