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



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



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



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.



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.
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Rebecca L
RL
Kusko
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
John F
JF
Brothers
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
John
J
Tedrow
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Kusum
K
Pandit
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Luai
L
Huleihel
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Catalina
C
Perdomo
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Gang
G
Liu
3 Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
Brenda
B
Juan-Guardela
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Daniel
D
Kass
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Sherry
S
Zhang
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Marc
M
Lenburg
4 Pulmonary & Critical Care Medicine, University of Michigan, Ann Arbor, Michigan.
Fernando
F
Martinez
5 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
John
J
Quackenbush
2 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
Frank
F
Sciurba
6 Mayo Clinic, Rochester, Minnesota; and.
Andrew
A
Limper
7 Pulmonary Sciences and Critical Care Medicine, UC Denver, Denver, Colorado.
Mark
M
Geraci
7 Pulmonary Sciences and Critical Care Medicine, UC Denver, Denver, Colorado.
Ivana
I
Yang
7 Pulmonary Sciences and Critical Care Medicine, UC Denver, Denver, Colorado.
David A
DA
Schwartz
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Jennifer
J
Beane
1 Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts.
Avrum
0000-0003-1467-0489
A
Spira
3 Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut.
Naftali
0000-0001-5917-4601
N
Kaminski
D000328:Adult; D004646:Emphysema / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
COPD; ILD; IPF; network; transcriptome