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miR-638 regulates gene expression networks associated with emphysematous lung destruction

Stephanie A Christenson12*, Corry-Anke Brandsma34, Joshua D Campbell15, Darryl A Knight67, Dmitri V Pechkovsky68, James C Hogg6, Wim Timens34, Dirkje S Postma49, Marc Lenburg15 and Avrum Spira15

Author Affiliations

1 Division of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, 72 East Concord Street Boston, MA 02118, USA

2 Department of Pulmonary and Critical Care Medicine, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA

3 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 Groningen, Netherlands

4 University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Hanzeplein 1, 9713 Groningen, Netherlands

5 Bioinformatics Program, Boston University, 44 Cummington Street Boston, MA 02215, USA

6 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

7 School of Biomedical Sciences and Pharmacy, University of Newcastle, University Drive Callaghan, New South Wales 2308, Australia

8 Respiratory Division, Department of Medicine, University of British Columbia, The Jack Bell Research Center, 2660 Oak Street Vancouver, BC V6H 3Z6, Canada

9 Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 Groningen, Netherlands

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Genome Medicine 2013, 5:114  doi:10.1186/gm519

Published: 31 December 2013

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.