Armstrong David A, Chen Youdinghuan, Dessaint John A, Aridgides Daniel S, Channon Jacqueline Y, Mellinger Diane L, Christensen Brock C, Ashare Alix
Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756;
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
Immunohorizons. 2019 Jul 2;3(7):274-281. doi: 10.4049/immunohorizons.1900042.
A number of pulmonary diseases occur with upper lobe predominance, including cystic fibrosis and smoking-related chronic obstructive pulmonary disease. In the healthy lung, several physiologic and metabolic factors exhibit disparity when comparing the upper lobe of the lung to lower lobe, including differences in oxygenation, ventilation, lymphatic flow, pH, and blood flow. In this study, we asked whether these regional differences in the lung are associated with DNA methylation changes in lung macrophages that could potentially lead to altered cell responsiveness upon subsequent environmental challenge. All analyses were performed using primary lung macrophages collected via bronchoalveolar lavage from healthy human subjects with normal pulmonary function. Epigenome-wide DNA methylation was examined via Infinium MethylationEPIC (850K) array and validated by targeted next-generation bisulfite sequencing. We observed 95 CpG loci with significant differential methylation in lung macrophages, comparing upper lobe to lower lobe (all false discovery rate < 0.05). Several of these genes, including , , , , and , have been implicated as participants in inflammatory/immune-related biological processes. Functionally, we identified phenotypic differences in oxygen use, comparing upper versus lower lung macrophages. Our results support a hypothesis that epigenetic changes, specifically DNA methylation, at a multitude of gene loci in lung macrophages are associated with metabolic differences regionally in lung.
许多肺部疾病以上叶为主，包括囊性纤维化和与吸烟相关的慢性阻塞性肺疾病。在健康肺脏中，与下叶相比，上叶在一些生理和代谢因素方面存在差异，包括氧合、通气、淋巴流动、pH值和血流等方面的差异。在本研究中，我们探究了肺脏中的这些区域差异是否与肺巨噬细胞中的DNA甲基化变化相关，而这种变化可能会在随后的环境挑战中导致细胞反应性改变。所有分析均使用通过支气管肺泡灌洗从肺功能正常的健康人类受试者中收集的原代肺巨噬细胞进行。通过Infinium MethylationEPIC（850K）阵列检测全基因组DNA甲基化，并通过靶向新一代亚硫酸氢盐测序进行验证。比较上叶和下叶的肺巨噬细胞，我们观察到95个CpG位点存在显著的差异甲基化（所有错误发现率<0.05）。其中一些基因，包括[此处原文缺失具体基因名称]，已被认为参与炎症/免疫相关的生物学过程。在功能上，我们比较了上肺和下肺巨噬细胞在氧气利用方面的表型差异。我们的结果支持这样一种假设，即肺巨噬细胞中多个基因位点的表观遗传变化，特别是DNA甲基化，与肺脏区域的代谢差异相关。
