Smoking-Induced Epigenetic Changes in the Lung: Role of DNA Demethylation

摘要 胞嘧啶甲基化（5-甲基胞嘧啶（MeC））以组织特异性方式调节基因表达。这些 甲基化标记是由DNA甲基转移酶（DNMT）引入的，DNMT催化DNA的从头甲基化。 CpG位点并维持DNA甲基化模式，以允许特定基因的激活和沉默。十 11种转运蛋白（泰特）催化α-酮戊二酸依赖性MeC氧化为5-羟甲基- 胞嘧啶（hmC）、5-甲酰基胞嘧啶（fC）和5-羧基胞嘧啶（caC）。这些氧化形式的MeC用作 去甲基化中间体，导致基因重新激活。此外，对大脑和胚胎的研究 干细胞已经表明，hmC、fC和caC可以被特异性蛋白质阅读器识别， 表观遗传学的功能胞嘧啶甲基化模式在正常体细胞组织中是稳定的，但在正常体细胞组织中， 在包括癌症、哮喘和自闭症在内的许多疾病中显著改变。确切地说， 癌症中的甲基化和羟甲基化导致肿瘤抑制基因的沉默和 原癌基因我们已经表明，慢性炎症和暴露于烟草亚硝胺诱导 肺癌A/J模型的早期表观遗传学变化。这些变化早在 肿瘤的形成，包括胞嘧啶甲基化，羟甲基化，甲基化和组蛋白 乙酰化然而，这些表观遗传变化的功能结果仍有待确定。这 研究计划的重点是研究肺中MeC、hmC、fC和caC的功能， 与吸烟和炎症相关的表观遗传变化，并阐明泰特的表观遗传功能 肺中的蛋白质。总之，这些研究将有助于我们理解正常的表观遗传 肺内的代谢机制及其对吸烟和炎症的反应。

Abstract 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 α-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.