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Am J Respir Crit Care Med. 2013 Feb 15;187(4):397-405. doi: 10.1164/rccm.201205-0888OC. Epub 2013 Jan 10.

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

Author information

1
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, College of Medicine, Davis Heart and Lung Research Institute, Columbus, OH, USA.

Abstract

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.

PMID:
23306545
PMCID:
PMC3603596
DOI:
10.1164/rccm.201205-0888OC
[Indexed for MEDLINE]
Free PMC Article

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