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

TitleIntegrated Genomics Reveals Convergent Transcriptomic Networks Underlying Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsKusko RL, Brothers JF, 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 DA, Beane J, Spira A, Kaminski N
JournalAm J Respir Crit Care Med
Volume194
Issue8
Pagination948-960
Date Published10/2016
ISSN1535-4970
KeywordsAdult, Emphysema, Female, Gene Regulatory Networks, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, I-kappa B Proteins, Idiopathic Pulmonary Fibrosis, Male, Membrane Proteins, Middle Aged, Nerve Tissue Proteins, Oligonucleotide Array Sequence Analysis, Platelet-Derived Growth Factor, Proto-Oncogene Proteins c-mdm2, Pulmonary Disease, Chronic Obstructive
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.

DOI10.1164/rccm.201510-2026OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID27104832
PubMed Central IDPMC5067817
Grant ListRC2 HL101715 / HL / NHLBI NIH HHS / United States
R01 HL127349 / HL / NHLBI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
T32 HL007035 / HL / NHLBI NIH HHS / United States
U01 HL108642 / HL / NHLBI NIH HHS / United States
P30 CA046934 / CA / NCI NIH HHS / United States
R21 HL121572 / HL / NHLBI NIH HHS / United States
R01 HL095393 / HL / NHLBI NIH HHS / United States