Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis

Duaa Dakhlallah, Kara Batte, Yijie Wang, Carmen Z Cantemir-Stone, Pearlly Yan, Gerard Nuovo, Adel Mikhail, Charles L Hitchcock, Valerie P Wright, S Patrick Nana-Sinkam, Melissa G Piper, Clay B Marsh
American Journal of Respiratory and Critical Care Medicine 2013 February 15, 187 (4): 397-405

RATIONALE: 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.

OBJECTIVES: We investigated the miR-17~92 cluster expression and its role in regulating DNA methylation events in IPF lung tissue.

METHODS: 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.

MEASUREMENTS AND MAIN RESULTS: 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.

CONCLUSIONS: 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.

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