Ren Lu, Chang Yan-Fen, Jiang Shi-He, Li Xiao-Hong, Cheng Hai-Peng
Clinical Nursing Teaching and Research Section, Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, China.
Medicine School, Zhengzhou University of Industrial Technology, Zhengzhou, China.
Front Cell Dev Biol. 2024 Jun 10;12:1416325. doi: 10.3389/fcell.2024.1416325. eCollection 2024.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease with a prognosis worse than lung cancer. It is a fatal lung disease with largely unknown etiology and pathogenesis, and no effective therapeutic drugs render its treatment largely unsuccessful. With continuous in-depth research efforts, the epigenetic mechanisms in IPF pathogenesis have been further discovered and concerned. As a widely studied mechanism of epigenetic modification, DNA methylation is primarily facilitated by DNA methyltransferases (DNMTs), resulting in the addition of a methyl group to the fifth carbon position of the cytosine base, leading to the formation of 5-methylcytosine (5-mC). Dysregulation of DNA methylation is intricately associated with the advancement of respiratory disorders. Recently, the role of DNA methylation in IPF pathogenesis has also received considerable attention. DNA methylation patterns include methylation modification and demethylation modification and regulate a range of essential biological functions through gene expression regulation. The Ten-Eleven-Translocation (TET) family of DNA dioxygenases is crucial in facilitating active DNA demethylation through the enzymatic conversion of the modified genomic base 5-mC to 5-hydroxymethylcytosine (5-hmC). TET2, a member of TET proteins, is involved in lung inflammation, and its protein expression is downregulated in the lungs and alveolar epithelial type II cells of IPF patients. This review summarizes the current knowledge of pathologic features and DNA methylation mechanisms of pulmonary fibrosis, focusing on the critical roles of abnormal DNA methylation patterns, DNMTs, and TET proteins in impacting IPF pathogenesis. Researching DNA methylation will enchance comprehension of the fundamental mechanisms involved in IPF pathology and provide novel diagnostic biomarkers and therapeutic targets for pulmonary fibrosis based on the studies involving epigenetic mechanisms.
特发性肺纤维化（IPF）是一种慢性、进行性且不可逆的间质性肺疾病，其预后比肺癌更差。它是一种病因和发病机制 largely 不明的致命性肺部疾病，由于缺乏有效的治疗药物，其治疗大多不成功。随着研究的不断深入，IPF 发病机制中的表观遗传机制已被进一步发现并受到关注。作为一种被广泛研究的表观遗传修饰机制，DNA 甲基化主要由 DNA 甲基转移酶（DNMTs）促进，导致在胞嘧啶碱基的第五个碳原子位置添加一个甲基基团，从而形成 5-甲基胞嘧啶（5-mC）。DNA 甲基化失调与呼吸系统疾病的进展密切相关。最近，DNA 甲基化在 IPF 发病机制中的作用也受到了相当大的关注。DNA 甲基化模式包括甲基化修饰和去甲基化修饰，并通过基因表达调控来调节一系列重要的生物学功能。DNA 双加氧酶的 Ten-Eleven-Translocation（TET）家族在促进活性 DNA 去甲基化方面起着关键作用，它通过将修饰的基因组碱基 5-mC 酶促转化为 5-羟甲基胞嘧啶（5-hmC）来实现。TET2 是 TET 蛋白家族的成员之一，参与肺部炎症，在 IPF 患者的肺组织和肺泡 II 型上皮细胞中其蛋白表达下调。本综述总结了目前关于肺纤维化病理特征和 DNA 甲基化机制的知识，重点关注异常 DNA 甲基化模式、DNMTs 和 TET 蛋白在影响 IPF 发病机制中的关键作用。基于涉及表观遗传机制的研究，对 DNA 甲基化的研究将增强对 IPF 病理所涉及基本机制的理解，并为肺纤维化提供新的诊断生物标志物和治疗靶点。
