National Heart and Lung Institute, Imperial College London, London, United Kingdom.
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
Am J Respir Crit Care Med. 2021 Oct 15;204(8):954-966. doi: 10.1164/rccm.202101-0004OC.
Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. To assess the role of epigenetic regulation of AMs during lung fibrosis. We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors ( = 14) and donors with IPF ( = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions ( = 11) and differentially methylated regions ( = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.
气道巨噬细胞（AMs）是肺部环境的关键调节者，与特发性肺纤维化（IPF）的发病机制有关，IPF 是一种致命的呼吸系统疾病，目前尚无治愈方法。然而，关于 AMs 在 IPF 中的表观遗传学知识有限。为了评估肺纤维化过程中 AMs 的表观遗传调控作用。我们使用 Illumina EPIC（850k）阵列对来自健康供体（n=14）和 IPF 供体（n=30）的分选 AMs 进行了 DNA 甲基化（DNAm）谱分析。通过使用参考髓样细胞 DNA 甲基组学进行细胞类型去卷积。我们的分析表明，表观遗传异质性是 IPF AMs 的一个关键特征。DNAm“时钟”分析表明，IPF AMs 中的表观遗传改变与加速衰老无关。在差异 DNAm 分析中，我们分别在健康和 IPF AMs 之间鉴定了许多差异甲基化位置（n=11）和差异甲基化区域（n=49）。差异甲基化位置和差异甲基化区域包含参与脂质（LPCAT1[溶血磷脂酰胆碱酰基转移酶 1]）和葡萄糖（PFKFB3[6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3]）代谢的基因，重要的是，DNAm 状态与 IPF 中的疾病严重程度相关。总之，我们的数据表明，表观基因组的变化与 IPF 肺部 AMs 的发育和功能有关。
