Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, College of Medicine, Davis Heart and Lung Research Institute, Columbus, OH, USA.
Am J Respir Crit Care Med. 2013 Feb 15;187(4):397-405. doi: 10.1164/rccm.201205-0888OC. Epub 2013 Jan 10.
Idiopathic pulmonary fibrosis (IPF) is a disease of progressive lung fibrosis with a high mortality rate. In organ repair and remodeling, epigenetic events are important. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and can target epigenetic molecules important in DNA methylation. The miR-17~92 miRNA cluster is critical for lung development and lung epithelial cell homeostasis and is predicted to target fibrotic genes and DNA methyltransferase (DNMT)-1 expression.
We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue.
Expression and DNA methylation patterns of miR-1792 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-1792 cluster and DNMT-1 expression was examined in vitro. Using a murine model of pulmonary fibrosis, we examined the therapeutic potential of the demethylating agent, 5'-aza-2'-deoxycytidine.
Compared with control samples, miR-1792 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-1792 promoter was increased. Several miRNAs from the miR-1792 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-1792 expression was reduced in the lungs of bleomycin-treated mice. Treatment with 5'-aza-2'-deoxycytidine in a murine bleomycin-induced pulmonary fibrosis model reduced fibrotic gene and DNMT-1 expression, enhanced miR-17~92 cluster expression, and attenuated pulmonary fibrosis.
This study provides insight into the pathobiology of IPF and identifies a novel epigenetic feedback loop between miR-17~92 and DNMT-1 in lung fibrosis.
特发性肺纤维化（IPF）是一种具有高死亡率的进行性肺纤维化疾病。在器官修复和重塑中，表观遗传事件很重要。微小 RNA（miRNA）在后转录水平上调节基因表达，并且可以靶向在 DNA 甲基化中重要的表观遗传分子。miR-17~92 微 RNA 簇对于肺发育和肺上皮细胞稳态很关键，并且被预测可以靶向纤维化基因和 DNA 甲基转移酶（DNMT）-1 的表达。
我们研究了 miR-17~92 簇在 IPF 肺组织中的表达及其对 DNA 甲基化事件的调控作用。
在人 IPF 肺组织和成纤维细胞以及纤维化的鼠肺组织中确定了 miR-1792 的表达和 DNA 甲基化模式。在体外研究了 miR-1792 簇与 DNMT-1 表达之间的关系。利用肺纤维化的小鼠模型，我们研究了去甲基化剂 5'-氮杂-2'-脱氧胞苷的治疗潜力。
与对照样本相比，IPF 患者的肺活检和肺成纤维细胞中 miR-1792 的表达降低，而 DNMT-1 表达和 miR-1792 启动子的甲基化增加。miR-1792 簇中的几个 miRNA 靶向 DNMT-1 的表达，导致负反馈环。同样，在博来霉素处理的小鼠的肺中 miR-1792 的表达也降低。在博来霉素诱导的肺纤维化的小鼠模型中，用 5'-氮杂-2'-脱氧胞苷治疗可降低纤维化基因和 DNMT-1 的表达，增强 miR-17~92 簇的表达，并减轻肺纤维化。
这项研究提供了对特发性肺纤维化发病机制的深入了解，并确定了肺纤维化中 miR-17~92 和 DNMT-1 之间的新的表观遗传反馈环。
