Integrative expression analysis identifies a novel interplay between CFTR and linc-SUMF1-2 that involves CF-associated gene dysregulation

Shunsuke Kamei; Kasumi Maruta; Haruka Fujikawa; Hirofumi Nohara; Keiko Ueno-Shuto; Yukihiro Tasaki; Ryunosuke Nakashima; Taisei Kawakami; Yuka Eto; Mary Ann Suico; Shingo Suzuki; Dieter C Gruenert; Jian-Dong Li; Hirofumi Kai; Tsuyoshi Shuto

doi:10.1016/j.bbrc.2018.12.152

Integrative expression analysis identifies a novel interplay between CFTR and linc-SUMF1-2 that involves CF-associated gene dysregulation

Biochem Biophys Res Commun. 2019 Feb 5;509(2):521-528. doi: 10.1016/j.bbrc.2018.12.152. Epub 2018 Dec 28.

Authors

Affiliations

¹ Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan; Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
² Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
³ Laboratory of Pharmacology, Division of Life Science, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan.
⁴ Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, 714 Petit Science Center, 100 Piedmont Ave SE, Atlanta, GA30303, USA.
⁵ Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Pressler St, Houston, TX77030, USA.
⁶ Head and Neck Stem Cell Lab, University of California, San Francisco, 2340 Sutter St, Box 1330, N331, San Francisco, CA, 94115, USA.
⁷ Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address: tshuto@gpo.kumamoto-u.ac.jp.

PMID: 30598261
DOI: 10.1016/j.bbrc.2018.12.152

Abstract

Cystic fibrosis transmembrane regulator (CFTR) is a cyclic AMP-dependent Cl^- channel, and its dysfunction, due to CFTR gene mutations, causes the lethal inherited disorder cystic fibrosis (CF). To date, widespread dysregulation of certain coding genes in CF airway epithelial cells is well studied and considered as the driver of pulmonary abnormality. However, the involvement of non-coding genes, novel classes of functional RNAs with little or no protein-coding capacity, in the regulation of CF-associated gene dysregulation is poorly understood. Here, we utilized integrative analyses of human transcriptome array (HTA) and characterized 99 coding and 91 non-coding RNAs that are dysregulated in CFTR-defective CF bronchial epithelial cell line CFBE41o-. Among these genes, the expression level of linc-SUMF1-2, an intergenic non-coding RNA (lincRNA) whose function is unknown, was inversely correlated with that of WT-CFTR and consistently higher in primary human CF airway epithelial cells (DHBE-CF). Further integrative analyses under linc-SUMF1-knockdown condition determined MXRA5, SEMA5A, CXCL10, AK022877, CTGF, MYC, AREG and LAMB3 as both CFTR- and linc-SUMF1-2-dependent dysregulated gene sets in CF airway epithelial cells. Overall, our analyses reveal linc-SUMF1-2 as a dysregulated non-coding gene in CF as well as CFTR-linc-SUMF1-2 axis as a novel regulatory pathway involved in CF-associated gene dysregulation.

Keywords: Airway epithelia; CFTR; Cystic fibrosis; Transcriptome; linc-SUMF1-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bronchi / cytology
Bronchi / metabolism
Cell Line
Cystic Fibrosis / genetics*
Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
Epithelial Cells / cytology
Epithelial Cells / metabolism*
Gene Expression Regulation*
Humans
RNA, Long Noncoding / genetics*
Transcriptome*

Substances

CFTR protein, human
RNA, Long Noncoding
Cystic Fibrosis Transmembrane Conductance Regulator