PUBLICATION

Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension

Authors
Sasagawa, S., Nishimura, Y., Sawada, H., Zhang, E., Okabe, S., Murakami, S., Ashikawa, Y., Yuge, M., Kawaguchi, K., Kawase, R., Mitani, Y., Maruyama, K., Tanaka, T.
ID
ZDB-PUB-160706-6
Date
2016
Source
Frontiers in pharmacology   7: 142 (Journal)
Registered Authors
Tanaka, Toshio
Keywords
CCDC80, COL1A1, EDN1, comparative transcriptome analysis, pulmonary arterial hypertension, systems pharmacology, weighted gene co-expression network analysis
MeSH Terms
none
PubMed
27375481 Full text @ Front Pharmacol
Abstract
Pulmonary arterial hypertension (PAH) is a heterogeneous disorder associated with a progressive increase in pulmonary artery resistance and pressure. Although various therapies have been developed, the 5-year survival rate of PAH patients remains low. There is thus an important need to identify novel genes that are commonly dysregulated in PAH of various etiologies and could be used as biomarkers and/or therapeutic targets. In this study, we performed comparative transcriptome analysis of five mammalian PAH datasets downloaded from a public database. We identified 228 differentially expressed genes (DEGs) from a rat PAH model caused by inhibition of vascular endothelial growth factor receptor under hypoxic conditions, 379 DEGs from a mouse PAH model associated with systemic sclerosis, 850 DEGs from a mouse PAH model associated with schistosomiasis, 1598 DEGs from one cohort of human PAH patients, and 4260 DEGs from a second cohort of human PAH patients. Gene-by-gene comparison identified four genes that were differentially upregulated or downregulated in parallel in all five sets of DEGs. Expression of coiled-coil domain containing 80 (CCDC80) and anterior gradient two genes was significantly increased in the five datasets, whereas expression of SMAD family member six and granzyme A was significantly decreased. Weighted gene co-expression network analysis revealed a connection between CCDC80 and collagen type I alpha 1 (COL1A1) expression. To validate the function of CCDC80 in vivo, we knocked out ccdc80 in zebrafish using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. In vivo imaging of zebrafish expressing a fluorescent protein in endothelial cells showed that ccdc80 deletion significantly increased the diameter of the ventral artery, a vessel supplying blood to the gills. We also demonstrated that expression of col1a1 and endothelin-1 mRNA was significantly decreased in the ccdc80-knockout zebrafish. Finally, we examined Ccdc80 immunoreactivity in a rat PAHmodel and found increased expression in the hypertrophied media and adventitia of the pre-acinar pulmonary arteries (PAs) and in the thickened intima, media, and adventitia of the obstructed intra-acinar PAs. These results suggest that increased expression of CCDC80 may be involved in the pathogenesis of PAH, potentially by modulating the expression of endothelin-1 and COL1A1.
Genes / Markers
Marker Marker Type Name
ccdc80GENEcoiled-coil domain containing 80
col1a1aGENEcollagen, type I, alpha 1a
edn1GENEendothelin 1
gapdhGENEglyceraldehyde-3-phosphate dehydrogenase
sfrp2GENEsecreted frizzled-related protein 2
slc45a2GENEsolute carrier family 45 member 2
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Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b4
    Insertion
    y1TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      ccdc80CRISPR1-ccdc80CRISPR
      1 - 1 of 1
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      Fish
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
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      Mapping
      No data available