Department of Environmental Health and Engineering and.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Am J Respir Cell Mol Biol. 2024 Mar;70(3):165-177. doi: 10.1165/rcmb.2023-0147OC.
Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of in COPD is due to increased DNA methylation site at the enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme . Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2'-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.
慢性阻塞性肺疾病（COPD）仍然是一个主要的公共卫生挑战，它在全球范围内极大地导致了死亡率和发病率。尽管人们早就认识到 COPD 中上皮细胞发生了改变，但很少关注针对它来改变疾病进程。因此，破坏 COPD 患者上皮细胞功能的机制还了解甚少。在这项研究中，我们试图确定细胞间粘附分子 E-钙黏蛋白的表观遗传重编程是否会破坏上皮细胞的完整性。通过减少这些表观遗传标记，我们可以恢复上皮细胞的完整性并挽救肺泡气腔的破坏。我们使用分化的正常和 COPD 来源的原代人呼吸道上皮细胞、基因操作的小鼠气管上皮细胞以及小鼠和人精密切割肺切片来评估表观遗传重编程的影响。我们表明，COPD 中 基因的缺失是由于 增强子 D 上的 DNA 甲基化位点增加所致，这是通过下调 ten-eleven 转位酶甲基胞嘧啶双加氧酶（TET） 引起的。增强子 D 区域的 DNA 甲基化增加会降低 RNA 聚合酶 II 结合的丰度。值得注意的是，用 DNA 去甲基化剂 5-氮杂-2'-脱氧胞苷处理源自 COPD 患者的人精密切割切片，可减少细胞损伤并减少病变组织中的气腔扩大。在这里，我们提出了一种新的机制，即针对表观遗传修饰来逆转人类 COPD 肺部的组织重塑，并为开发一种疾病修饰靶点提供了概念验证。
