title: Comparative Transcriptome Analysis Identifies CCDC80 as a Novel Gene Associated with Pulmonary Arterial Hypertension.
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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Sasagawa
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, TsuJapan; Mie University Medical Zebrafish Research Center, TsuJapan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, TsuJapan; Department of Omics Medicine, Mie University Industrial Technology Innovation Institute, TsuJapan; Department of Bioinformatics, Mie University Life Science Research Center, TsuJapan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Shiko
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ashikawa
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yuge
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kawase
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, TsuJapan; Mie University Medical Zebrafish Research Center, TsuJapan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, TsuJapan; Department of Omics Medicine, Mie University Industrial Technology Innovation Institute, TsuJapan; Department of Bioinformatics, Mie University Life Science Research Center, TsuJapan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
keywords: CCDC80; COL1A1; EDN1; comparative transcriptome analysis; pulmonary arterial hypertension; systems pharmacology; weighted gene co-expression network analysis