title: miR-638 regulates gene expression networks associated with emphysematous lung destruction.
abstract: BACKGROUND
  Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks.
  
  
  METHODS
  We profiled microRNAs in different regions of the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified by mean linear intercept. Whole genome microRNA and gene expression data were integrated in the same samples to build co-expression networks. Candidate microRNAs were perturbed in human lung fibroblasts in order to validate these networks.
  
  
  RESULTS
  The expression levels of 63 microRNAs (P < 0.05) were altered with regional emphysema. A subset, including miR-638, miR-30c, and miR-181d, had expression levels that were associated with those of their predicted mRNA targets. Genes correlated with these microRNAs were enriched in pathways associated with emphysema pathophysiology (for example, oxidative stress and accelerated aging). Inhibition of miR-638 expression in lung fibroblasts led to modulation of these same emphysema-related pathways. Gene targets of miR-638 in these pathways were amongst those negatively correlated with miR-638 expression in emphysema.
  
  
  CONCLUSIONS
  Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression pathways related to the oxidative stress response and aging in emphysematous lung tissue and lung fibroblasts.
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street Boston, MA 02118, USA ; Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Christenson
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands ; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street Boston, MA 02215, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Campbell
authors.affiliation: UBC James Hogg Research Centre, Institute for Heart and Lung Health, St Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St Vancouver, BC V6Z 1Y6, Canada ; School of Biomedical Sciences and Pharmacy, University of Newcastle, University Drive Callaghan, New South Wales 2308, Australia.
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.affiliation: UBC James Hogg Research Centre, Institute for Heart and Lung Health, St Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St Vancouver, BC V6Z 1Y6, Canada ; Respiratory Division, Department of Medicine, University of British Columbia, The Jack Bell Research Center, 2660 Oak Street Vancouver, BC V6H 3Z6, Canada.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Pechkovsky
authors.affiliation: UBC James Hogg Research Centre, Institute for Heart and Lung Health, St Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia, 1081 Burrard St Vancouver, BC V6Z 1Y6, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Hogg
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands ; University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Hanzeplein 1, 9713 Groningen, Netherlands ; Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 Groningen, Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street Boston, MA 02215, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Lenburg
authors.affiliation: Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street Boston, MA 02118, USA ; Bioinformatics Program, Boston University, 44 Cummington Street Boston, MA 02215, USA.
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira