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

作者：Rebecca Kusko, John F. Brothers, John Tedrow, Kusum Pandit, Luai Huleihel, Catalina Perdomo, Gang Liu, Brenda Juan-Guardela, Daniel J. Kass, Sherry Zhang, Marc E. Lenburg, Fernando J. Martínez, John Quackenbush, Frank C. Sciurba, Andrew H. Limper, Mark W. Geraci, Ivana V. Yang, David A. Schwartz, Jennifer Beane, Avrum Spira, Naftali Kaminski · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2016 · DOI：10.1164/rccm.201510-2026oc · 被引用次数：130 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Chronic Obstructive Pulmonary Disease (COPD) Research、Neonatal Respiratory Health Research

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 diseas...