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

TitleEpigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis
Publication TypeJournal Article
Year of Publication2013
AuthorsDakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G, Mikhail A, Hitchcock CL, Wright VP, S Nana-Sinkam P, Piper MG, Marsh CB
JournalAm J Respir Crit Care Med
Volume187
Issue4
Pagination397-405
Date Published2013 Feb 15
ISSN1535-4970
KeywordsAnimals, Azacitidine, Cells, Cultured, Disease Models, Animal, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, Epigenomics, Fibroblasts, Gene Expression, Humans, Idiopathic Pulmonary Fibrosis, Mice, Mice, Inbred C57BL, MicroRNAs, Real-Time Polymerase Chain Reaction, Repressor Proteins
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.

DOI10.1164/rccm.201205-0888OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID23306545
PubMed Central IDPMC3603596
Grant ListHL067176 / HL / NHLBI NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
R01 HL102464 / HL / NHLBI NIH HHS / United States
R01 HL109481 / HL / NHLBI NIH HHS / United States