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Am J Respir Crit Care Med. 2016 Oct 15;194(8):948-960.

Integrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.

Author information

1
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
2
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
3 Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
4
4 Pulmonary & Critical Care Medicine, University of Michigan, Ann Arbor, Michigan.
5
5 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
6
6 Mayo Clinic, Rochester, Minnesota; and.
7
7 Pulmonary Sciences and Critical Care Medicine, UC Denver, Denver, Colorado.

Abstract

RATIONALE:

Despite shared environmental exposures, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease are usually studied in isolation, and the presence of shared molecular mechanisms is unknown.

OBJECTIVES:

We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and IPF.

METHODS:

We defined the transcriptional repertoire of chronic obstructive pulmonary disease, IPF, or normal histology lungs using RNA-seq (n = 87).

MEASUREMENTS AND MAIN RESULTS:

Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n = 193). Immunohistochemistry confirmed overexpression of HIF1A, MDM2, and NFKBIB members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/hypoxia pathway-associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared with control and validated these findings by quantitative polymerase chain reaction and the nCounter Analysis System on an independent sample set (n = 193). Finally, by integrating parallel microRNA and mRNA-Seq data on the same samples, we identified MIR96 as a key novel regulatory hub in the p53/hypoxia gene-expression network and confirmed that modulation of MIR96 in vitro recapitulates the disease-associated gene-expression network.

CONCLUSIONS:

Our results suggest convergent transcriptional regulatory hubs in diseases as varied phenotypically as chronic obstructive pulmonary disease and IPF and suggest that these hubs may represent shared key responses of the lung to environmental stresses.

KEYWORDS:

COPD; ILD; IPF; network; transcriptome

PMID:
27104832
PMCID:
PMC5067817
DOI:
10.1164/rccm.201510-2026OC
[Indexed for MEDLINE]
Free PMC Article

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