Integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis

Rebecca L. Kusko, John F. Brothers, John Tedrow, Kusum Pandit, Luai Huleihel, Catalina Perdomo, Gang Liu, Brenda Juan-Guardela, Daniel Kass, Sherry Zhang, Marc Lenburg, Fernando Martinez, John Quackenbush, Frank Sciurba, Andrew Limper, Mark Geraci, Ivana Yang, David A. Schwartz, Jennifer Beane, Avrum SpiraNaftali Kaminski

Research output: Contribution to journalArticle

44 Scopus citations

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: Weapplied 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 parallelmicroRNA andmRNA-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.

Original languageEnglish (US)
Pages (from-to)948-960
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume194
Issue number8
DOIs
StatePublished - Oct 15 2016

Keywords

  • COPD
  • ILD
  • IPF
  • Network
  • Transcriptome

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Kusko, R. L., Brothers, J. F., Tedrow, J., Pandit, K., Huleihel, L., Perdomo, C., Liu, G., Juan-Guardela, B., Kass, D., Zhang, S., Lenburg, M., Martinez, F., Quackenbush, J., Sciurba, F., Limper, A., Geraci, M., Yang, I., Schwartz, D. A., Beane, J., ... Kaminski, N. (2016). Integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. American journal of respiratory and critical care medicine, 194(8), 948-960. https://doi.org/10.1164/rccm.201510-2026OC