Epigenetic Regulation of miR-17∼92 Contributes to the Pathogenesis of Pulmonary Fibrosis

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 methylati...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2013-02, Vol.187 (4), p.397-405
Main Authors: DAKHLALLAH, Duaa, BATTE, Kara, PIPER, Melissa G, MARSH, Clay B, YIJIE WANG, CANTEMIR-STONE, Carmen Z, YAN, Pearlly, NUOVO, Gerard, MIKHAIL, Adel, HITCHCOCK, Charles L, WRIGHT, Valerie P, PATRICK NANA-SINKAM, S
Format: Article
Language:English
Subjects:
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Azacitidine - analogs & derivatives
Biological and medical sciences
Cells, Cultured
Chronic obstructive pulmonary disease
Decitabine
Disease Models, Animal
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA methylation
DNA Methylation - genetics
Epigenetics
Epigenomics - methods
Fibroblasts
Fibroblasts - metabolism
Gene expression
Gene Expression - genetics
Homeostasis
Humans
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - metabolism
Intensive care medicine
Medical sciences
Mice
Mice, Inbred C57BL
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
Pathogenesis
Pneumology
Polymerase chain reaction
Pulmonary fibrosis
Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases
Real-Time Polymerase Chain Reaction - methods
Repressor Proteins - genetics
Repressor Proteins - metabolism
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Summary: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-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. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201205-0888oc