Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2012;7(4):e33770. doi: 10.1371/journal.pone.0033770. Epub 2012 Apr 10.
Idiopathic Pulmonary Fibrosis (IPF) is characterized by profound changes in the lung phenotype including excessive extracellular matrix deposition, myofibroblast foci, alveolar epithelial cell hyperplasia and extensive remodeling. The role of epigenetic changes in determining the lung phenotype in IPF is unknown. In this study we determine whether IPF lungs exhibit an altered global methylation profile.
METHODOLOGY/PRINCIPAL FINDINGS: Immunoprecipitated methylated DNA from 12 IPF lungs, 10 lung adenocarcinomas and 10 normal histology lungs was hybridized to Agilent human CpG Islands Microarrays and data analysis was performed using BRB-Array Tools and DAVID Bioinformatics Resources software packages. Array results were validated using the EpiTYPER MassARRAY platform for 3 CpG islands. 625 CpG islands were differentially methylated between IPF and control lungs with an estimated False Discovery Rate less than 5%. The genes associated with the differentially methylated CpG islands are involved in regulation of apoptosis, morphogenesis and cellular biosynthetic processes. The expression of three genes (STK17B, STK3 and HIST1H2AH) with hypomethylated promoters was increased in IPF lungs. Comparison of IPF methylation patterns to lung cancer or control samples, revealed that IPF lungs display an intermediate methylation profile, partly similar to lung cancer and partly similar to control with 402 differentially methylated CpG islands overlapping between IPF and cancer. Despite their similarity to cancer, IPF lungs did not exhibit hypomethylation of long interspersed nuclear element 1 (LINE-1) retrotransposon while lung cancer samples did, suggesting that the global hypomethylation observed in cancer was not typical of IPF.
CONCLUSIONS/SIGNIFICANCE: Our results provide evidence that epigenetic changes in IPF are widespread and potentially important. The partial similarity to cancer may signify similar pathogenetic mechanisms while the differences constitute IPF or cancer specific changes. Elucidating the role of these specific changes will potentially allow better understanding of the pathogenesis of IPF.
特发性肺纤维化（IPF）的特点是肺表型发生深刻变化，包括细胞外基质过度沉积、肌成纤维细胞灶、肺泡上皮细胞增生和广泛重塑。表观遗传变化在决定 IPF 中肺表型的作用尚不清楚。在这项研究中，我们确定 IPF 肺是否表现出改变的全局甲基化谱。
方法/主要发现：从 12 例 IPF 肺、10 例肺腺癌和 10 例正常组织肺中免疫沉淀甲基化 DNA，与安捷伦人类 CpG 岛微阵列杂交，使用 BRB-Array Tools 和 DAVID 生物信息学资源软件包进行数据分析。使用 EpiTYPER MassARRAY 平台对 3 个 CpG 岛进行了阵列结果验证。IPF 与对照肺之间有 625 个 CpG 岛存在差异甲基化，估计错误发现率小于 5%。与差异甲基化 CpG 岛相关的基因参与细胞凋亡、形态发生和细胞生物合成过程的调节。三个基因（STK17B、STK3 和 HIST1H2AH）启动子低甲基化，在 IPF 肺中表达增加。将 IPF 的甲基化模式与肺癌或对照样本进行比较，结果显示 IPF 肺显示出中间甲基化谱，部分与肺癌相似，部分与对照相似，有 402 个差异甲基化 CpG 岛重叠。尽管与癌症相似，但 IPF 肺没有表现出长散在核元件 1（LINE-1）反转录转座子的低甲基化，而肺癌样本则有，这表明癌症中观察到的全局低甲基化并不是 IPF 的典型特征。
结论/意义：我们的研究结果提供了证据，表明 IPF 中的表观遗传变化是广泛存在的，可能具有重要意义。与癌症的部分相似可能意味着类似的发病机制，而差异则构成 IPF 或癌症的特异性变化。阐明这些特异性变化的作用可能会更好地理解 IPF 的发病机制。
