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)以组织特异性的方式调节基因表达。这些 甲基化标记是由DNA甲基转移酶(DNMT)引入的，它催化 CpG位点和维持DNA甲基化模式，以允许特定基因的激活和沉默。十 11种易位蛋白(Tet)催化α-酮戊二酸依赖的MEC氧化生成5-羟甲基-2-甲基-3-甲基-4-羟甲基-2，5-羟甲基-2，4，4，5-二羟甲基-4，4，5-二羟甲基-4，4，5-二羟甲基-4，4 胞嘧啶(HMC)、5-甲酰胞嘧啶(FC)和5-羧基胞嘧啶(CAC)。这些氧化形式的MEC可用作 去甲基化的中间产物，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可以被特定的蛋白质阅读器识别，并可能具有 它们自身的表观遗传功能。胞嘧啶甲基化模式在正常的体细胞组织中是稳定的，但 在包括癌症、哮喘和自闭症在内的许多疾病中都发生了显著变化。具体地说，扰乱的DNA 癌症中的甲基化和羟甲基化导致抑癌基因沉默和激活 原癌基因。我们已经证明，慢性炎症和暴露在烟草亚硝胺中会导致 肺癌A/J模型的早期表观遗传学改变。这些变化是可以检测到的，早在 肿瘤的形成，包括胞嘧啶甲基化、羟甲基化、甲酰化和组蛋白的变化 乙酰化。然而，这些表观遗传变化的功能结果仍有待确定。这 研究计划侧重于研究MEC、HMC、Fc和CAC在肺中的功能，表征 与吸烟和炎症相关的表观遗传学改变以及Tet的表观遗传学功能 肺部的蛋白质。综上所述，这些研究将有助于我们理解正常的表观遗传学 肺中的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.