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- Title
Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis.
- Authors
Dakhlallah, Duaa; Batte, Kara; Wang, Yijie; Cantemir-Stone, Carmen Z; Yan, Pearlly; Nuovo, Gerard; Mikhail, Adel; Hitchcock, Charles L; Wright, Valerie P; Nana-Sinkam, S Patrick; Piper, Melissa G; Marsh, Clay B
- Abstract
<bold>Rationale: </bold>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.<bold>Objectives: </bold>We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue.<bold>Methods: </bold>Expression and DNA methylation patterns of miR-17~92 were determined in human IPF lung tissue and fibroblasts and fibrotic mouse lung tissue. The relationship between the miR-17~92 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.<bold>Measurements and Main Results: </bold>Compared with control samples, miR-17~92 expression was reduced in lung biopsies and lung fibroblasts from patients with IPF, whereas DNMT-1 expression and methylation of the miR-17~92 promoter was increased. Several miRNAs from the miR-17~92 cluster targeted DNMT-1 expression resulting in a negative feedback loop. Similarly, miR-17~92 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.<bold>Conclusions: </bold>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.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2013, Vol 187, Issue 4, p397
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201205-0888OC