title: Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, College of Medicine, Davis Heart and Lung Research Institute, Columbus, OH, USA.
authors.forename: Duaa
authors.initials: D
authors.lastname: Dakhlallah
authors.forename: Kara
authors.initials: K
authors.lastname: Batte
authors.forename: Yijie
authors.initials: Y
authors.lastname: Wang
authors.forename: Carmen Z
authors.initials: CZ
authors.lastname: Cantemir-Stone
authors.forename: Pearlly
authors.initials: P
authors.lastname: Yan
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Adel
authors.initials: A
authors.lastname: Mikhail
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hitchcock
authors.forename: Valerie P
authors.initials: VP
authors.lastname: Wright
authors.forename: S Patrick
authors.initials: SP
authors.lastname: Nana-Sinkam
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Piper
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D000077209:Decitabine; D004195:Disease Models, Animal; D057890:Epigenomics / Q000379:methods; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D062085:RNA, Long Noncoding; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C411744:DMAP1 protein, human; C568997:MIR17HG, human; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D012097:Repressor Proteins; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine