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http://dx.doi.org/10.14348/molcells.2019.2442

Identification of Putative Regulatory Alterations Leading to Changes in Gene Expression in Chronic Obstructive Pulmonary Disease  

Kim, Dong-Yeop (Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology)
Kim, Woo Jin (Department of Internal Medicine, School of Medicine, Kangwon National University)
Kim, Jung-Hyun (Department of Internal Medicine, School of Medicine, Kangwon National University)
Hong, Seok-Ho (Department of Internal Medicine, School of Medicine, Kangwon National University)
Choi, Sun Shim (Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology)
Publication Information
Molecules and Cells / v.42, no.4, 2019 , pp. 333-344 More about this Journal
Abstract
Various genetic and environmental factors are known to be associated with chronic obstructive pulmonary disease (COPD). We identified COPD-related differentially expressed genes (DEGs) using 189 samples accompanying either adenocarcinoma (AC) or squamous cell carcinoma (SC), comprising 91 normal and 98 COPD samples. DEGs were obtained from the intersection of two DEG sets separately identified for AC and SC to exclude the influence of different cancer backgrounds co-occurring with COPD. We also measured patient samples named group 'I', which were unable to be determined as normal or COPD based on alterations in gene expression. The Gene Ontology (GO) analysis revealed significant alterations in the expression of genes categorized with the 'cell adhesion', 'inflammatory response', and 'mitochondrial functions', i.e., well-known functions related to COPD, in samples from patients with COPD. Multi-omics data were subsequently integrated to decipher the upstream regulatory changes linked to the gene expression alterations in COPD. COPD-associated expression quantitative trait loci (eQTLs) were located at the upstream regulatory regions of 96 DEGs. Additionally, 45 previously identified COPD-related miRNAs were predicted to target 66 of the DEGs. The eQTLs and miRNAs might affect the expression of 'respiratory electron transport chain' genes and 'cell proliferation' genes, respectively, while both eQTLs and miRNAs might affect the expression of 'apoptosis' genes. We think that our present study will contribute to our understanding of the molecular etiology of COPD accompanying lung cancer.
Keywords
COPD; differentially expressed genes; lung cancer; regulatory alterations; STX8;
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1 Huh, J.W., Kim, S., Lee, J.H., Lee, J., Van Ta, Q., Kim, M., Oh, Y., Lee, Y., and Lee, S. (2011). Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am. J. Physiol.-lung C. 301, L255-L266.   DOI
2 Jeong, I., Lim, J., Oh, D.K., Kim, W.J., and Oh, Y. (2018). Gene expression profile of human lung in a relatively early stage of COPD with emphysema. Int. J. Chronic. Obstr. 13, 2643.
3 Ward, L.D., and Kellis, M. (2015). HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res. 44, D877-D881.   DOI
4 Wu, G., Feng, X., and Stein, L. (2010). A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 11, R53.   DOI
5 Zhang, L., Li, S., Choi, Y., Lee, J., Gong, Z., Liu, X., Pei, Y., Jiang, A., Ye, M., and Mao, M. (2017). Systematic identification of cancer-related long noncoding RNAs and aberrant alternative splicing of quintuple-negative lung adenocarcinoma through RNA-Seq. Lung Cancer 109, 21-27.   DOI
6 Kim, Y., Kim, J., Huh, J.W., Lee, S.W., Choi, S.J., and Oh, Y. (2015). The therapeutic effects of optimal dose of mesenchymal stem cells in a murine model of an elastase induced-emphysema. Tuberc. Respir. Dis. 78, 239-245.   DOI
7 Kim, W.J., and Lee, C.Y. (2017). Environmental exposures and chronic obstructive pulmonary disease. Mol. Cellular Toxicol. 13, 251-255.   DOI
8 Kim, W.J., Lim, J.H., Hong, Y., Hong, S., Bang, C.Y., Lee, J.S., Oh, Y., and Kim, J.H. (2017). Altered miRNA expression in lung tissues of patients with chronic obstructive pulmonary disease. Mol. Cellular Toxicol. 13, 207-212.   DOI
9 Kim, W.J., Lim, J.H., Lee, J.S., Lee, S., Kim, J.H., and Oh, Y. (2015). Comprehensive analysis of transcriptome sequencing data in the lung tissues of COPD subjects. Int. J. Genomics 2015, 206937.
10 Kim, D.H., Nelson, H.H., Wiencke, J.K., Zheng, S., Christiani, D.C., Wain, J.C., Mark, E.J., and Kelsey, K.T. (2001). p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res. 61, 3419-3424.
11 Kim, W.J., and Lee, S.D. (2015). Candidate genes for COPD: current evidence and research. Int. J. Chron. Obstruct Pulmon. Dis. 10, 2249-2255.
12 Lawless, M.W., O'byrne, K.J., and Gray, S.G. (2009). Oxidative stress induced lung cancer and COPD: opportunities for epigenetic therapy. J. Cell Mol. Med. 13, 2800-2821.   DOI
13 Lundback, B., Lindberg, A., Lindstrom, M., Ronmark, E., Jonsson, A.C., Jonsson, E., Larsson, L.G., Andersson, S., Sandstrom, T., Larsson, K., et al. (2003). Not 15 but 50% of smokers develop COPD?-Report from the obstructive lung disease in northern sweden studies. Respir. Med. 97, 115-122.   DOI
14 Aaron, S.D., Vandemheen, K.L., Fergusson, D., Maltais, F., Bourbeau, J., Goldstein, R., Balter, M., O'Donnell, D., McIvor, A., and Sharma, S. (2007). Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann. Intern. Med. 146, 545-555.   DOI
15 Agusti, A., Edwards, L.D., Rennard, S.I., MacNee, W., Tal-Singer, R., Miller, B.E., Vestbo, J., Lomas, D.A., Calverley, P.M., and Wouters, E. (2012). Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PloS One 7, e37483.   DOI
16 Lee, H., Han, S., Rhee, H., Park, J.H., Lee, J.S., Oh, Y., Choi, S.S., Shin, S., and Kim, W.J. (2015). Differential expression of microRNAs and their target genes in non-small-cell lung cancer. Mol. Med. Rep. 11, 2034-2040.   DOI
17 Lee, K.W., and Pausova, Z. (2013). Cigarette smoking and DNA methylation. Front. Genet. 4, 132.   DOI
18 Lonsdale, J., Thomas, J., Salvatore, M., Phillips, R., Lo, E., Shad, S., Hasz, R., Walters, G., Garcia, F., and Young, N. (2013). The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580.   DOI
19 Mannino, D.M., and Buist, A.S. (2007). Global burden of COPD: risk factors, prevalence, and future trends. The Lancet 370, 765-773.   DOI
20 Mannino, D.M., Ford, E.S., and Redd, S.C. (2003). Obstructive and restrictive lung disease and markers of inflammation: data from the third national health and nutrition examination. Am. J. Med. 114, 758-762.   DOI
21 Novak, J.P., Sladek, R., and Hudson, T.J. (2002). Characterization of variability in large-scale gene expression data: implications for study design. Genomics 79, 104-113.   DOI
22 Ocampo-Candiani, J., Salinas-Santander, M., Trevino, V., Ortiz-Lopez, R., Ocampo-Garza, J., and Sanchez-Dominguez, C.N. (2018). Evaluation of skin expression profiles of patients with vitiligo treated with narrow-band UVB therapy by targeted RNA-seq. An. Bras. Dermatol. 93, 843-851.   DOI
23 Repapi, E., Sayers, I., Wain, L.V., Burton, P.R., Johnson, T., Obeidat, M., Zhao, J.H., Ramasamy, A., Zhai, G., and Vitart, V. (2010). Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42, 36.   DOI
24 Pinero, J., Bravo, A., Queralt-Rosinach, N., Gutierrez-Sacristan, A., Deu-Pons, J., Centeno, E., Garcia-Garcia, J., Sanz, F., and Furlong, L.I. (2017). DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 4, D833-D839.
25 Rabe, K.F., Hurd, S., Anzueto, A., Barnes, P.J., Buist, S.A., Calverley, P., Fukuchi, Y., Jenkins, C., Rodriguez-Roisin, R., and Van Weel, C. (2007). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 176, 532-555.   DOI
26 Rangasamy, T., Misra, V., Zhen, L., Tankersley, C.G., Tuder, R.M., and Biswal, S. (2009). Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. Am. J. Physiol.-lung C. 296, L888-L900.   DOI
27 Russell, K.E., Chung, K.F., Clarke, C.J., Durham, A.L., Mallia, P., Footitt, J., Johnston, S.L., Barnes, P.J., Hall, S.R., and Simpson, K.D. (2016). The MIF antagonist ISO-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of COPD. PLoS One 11, e0146102.   DOI
28 Sakao, S., Tatsumi, K., Hashimoto, T., Igari, H., Shino, Y., Shirasawa, H., and Kuriyama, T. (2003). Vascular endothelial growth factor and the risk of smoking-related COPD. Chest 124, 323-327.   DOI
29 Sandford, A.J., Chagani, T., Weir, T.D., and Pare, P.D. (1998). ${\alpha}1$-antichymotrypsin mutations in patients with chronic obstructive pulmonary disease. Dis. Markers 13, 257-260.   DOI
30 Artigas, M.S., Loth, D.W., Wain, L.V., Gharib, S.A., Obeidat, M., Tang, W., Zhai, G., Zhao, J.H., Smith, A.V., and Huffman, J.E. (2011). Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat. Genet. 43, 1082.   DOI
31 Barnett, M. (2005). Chronic obstructive pulmonary disease: a phenomenological study of patients' experiences. J. Clin. Nurs. 14, 805-812.   DOI
32 Belinsky, S.A., Palmisano, W.A., Gilliland, F.D., Crooks, L.A., Divine, K.K., Winters, S.A., Grimes, M.J., Harms, H.J., Tellez, C.S., Smith, T.M., et al. (2002). Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res. 62, 2370-2377.
33 Buist, A.S., Vollmer, W., and McBurnie, M. (2008). Worldwide burden of COPD in high-and low-income countries. Part I. The Burden of Obstructive Lung Disease (BOLD) Initiative [State of the art series. Chronic obstructive pulmonary disease in high-and low-income countries. Edited by G. Marks and M. Chan-Yeung. Number 6 in the series]. Int. J. Tuberc. Lung Dis. 12, 703-708.
34 Spira, A., Beane, J.E., Shah, V., Steiling, K., Liu, G., Schembri, F., Gilman, S., Dumas, Y., Calner, P., and Sebastiani, P. (2007). Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat. Med. 13, 361.   DOI
35 Schamberger, A.C., Mise, N., Meiners, S., and Eickelberg, O. (2014). Epigenetic mechanisms in COPD: implications for pathogenesis and drug discovery. Expert Opin. Drug Discov. 9, 609-628.   DOI
36 She, W.B., Liu, X.S., Ni, W., Chen, S.X., and Xu, Y.J. (2012). The expression of macrophage migration inhibition factor in pulmonary tissues of smokers with or without chronic obstructive pulmonary disease. Zhonghua Nei Ke Za Zhi 51, 863-866.
37 Smith, C.A., and Harrison, D.J. (1997). Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. The Lancet 350, 630-633.   DOI
38 Steiling, K., Van Den Berge, M., Hijazi, K., Florido, R., Campbell, J., Liu, G., Xiao, J., Zhang, X., Duclos, G., and Drizik, E. (2013). A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am. J. Respir. Crit. Care Med. 187, 933-942.   DOI
39 Stoller, J.K., and Aboussouan, L.S. (2005). ${\alpha}1$-antitrypsin deficiency. The Lancet 365, 2225-2236.   DOI
40 Calverley, P.M., Anderson, J.A., Celli, B., Ferguson, G.T., Jenkins, C., Jones, P.W., Yates, J.C., and Vestbo, J. (2007). Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 775-789.   DOI
41 Cavarra, E., Bartalesi, B., Lucattelli, M., Fineschi, S., Lunghi, B., Gambelli, F., Ortiz, L.A., Martorana, P.A., and Lungarella, G. (2001). Effects of cigarette smoke in mice with different levels of ${\alpha}1$-proteinase inhibitor and sensitivity to oxidants. Am. J. Respir. Crit. Care Med. 164, 886-890.   DOI
42 Anderson, G.P., and Bozinovski, S. (2003). Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol. Sci. 24, 71-76.   DOI
43 Foreman, M.G., Campos, M., and Celedon, J.C. (2012). Genes and chronic obstructive pulmonary disease. Medical Clinics 96, 699-711.
44 Stone, P.J., Calore, J.D., McGowan, S.E., Bernardo, J., Snider, G.L., and Franzblau, C. (1983). Functional alpha 1-protease inhibitor in the lower respiratory tract of cigarette smokers is not decreased. Science 221, 1187-1189.   DOI
45 Subramanian, A., Tamayo, P., Mootha, V.K., Mukherjee, S., Ebert, B.L., Gillette, M.A., Paulovich, A., Pomeroy, S.L., Golub, T.R., Lander, E.S., et al. (2005). Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545-15550.   DOI
46 Chen, Z., Kim, H.P., Ryter, S.W., and Choi, A.M. (2008). Identifying targets for COPD treatment through gene expression analyses. Int. J. Chron. Obstruct. Pulmon. Dis. 3, 359.   DOI
47 Chou, C., Shrestha, S., Yang, C., Chang, N., Lin, Y., Liao, K., Huang, W., Sun, T., Tu, S., and Lee, W. (2017). miRTarBase update 2018: a resource for experimentally validated microRNA-target interactions. Nucleic Acids Res. 46, D296-D302.   DOI
48 Fabbri, L.M., Romagnoli, M., Corbetta, L., Casoni, G., Busljetic, K., Turato, G., Ligabue, G., Ciaccia, A., Saetta, M., and Papi, A. (2003). Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 167, 418-424.   DOI
49 Swanney, M.P., Ruppel, G., Enright, P.L., Pedersen, O.F., Crapo, R.O., Miller, M.R., Jensen, R.L., Falaschetti, E., Schouten, J.P., Hankinson, J.L., et al. (2008). Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax 63, 1046-1051.   DOI
50 Suki, B., Bartolak-Suki, E., and Rocco, P.R. (2017). Elastase-induced lung emphysema models in mice. In: Borel F., Mueller C. (eds) Alpha-1 Antitrypsin Deficiency. (New York: Humana Press) pp. 67-75.
51 Trapnell, C., Pachter, L., and Salzberg, S.L. (2009). TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105-1111.   DOI
52 Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D.R., Pimentel, H., Salzberg, S.L., Rinn, J.L., and Pachter, L. (2012). Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat. Protoc. 7, 562.   DOI
53 Huang, D.W., Sherman, B.T., and Lempicki, R.A. (2008). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44.   DOI
54 Hardin, M., and Silverman, E.K. (2014). Chronic obstructive pulmonary disease genetics: a review of the past and a look into the future. Int. J. Chron. Obstruct. Pulmon. Dis. 1, 33-46.
55 Hartigan, J.A., and Wong, M.A. (1979). Algorithm AS 136: A k-means clustering algorithm. J. R. Stat. Soc. C-Appl. 28, 100-108.
56 Hobbs, B.D., De Jong, K., Lamontagne, M., Bosse, Y., Shrine, N., Artigas, M.S., Wain, L.V., Hall, I.P., Jackson, V.E., and Wyss, A.B. (2017). Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat. Genet. 49, 426.   DOI
57 Huber, W., Carey, V.J., Gentleman, R., Anders, S., Carlson, M., Carvalho, B.S., Bravo, H.C., Davis, S., Gatto, L., and Girke, T. (2015). Orchestrating high-throughput genomic analysis with bioconductor. Nat. Methods 12, 115.   DOI
58 Wang, I., Stepaniants, S., Boie, Y., Mortimer, J.R., Kennedy, B., Elliott, M., Hayashi, S., Loy, L., Coulter, S., and Cervino, S. (2008). Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am. J. Respir. Crit. Care Med. 177, 402-411.   DOI
59 Trapnell, C., Williams, B.A., Pertea, G., Mortazavi, A., Kwan, G., Van Baren, M.J., Salzberg, S.L., Wold, B.J., and Pachter, L. (2010). Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28, 511.   DOI
60 Vestbo, J., Hurd, S.S., Agusti, A.G., Jones, P.W., Vogelmeier, C., Anzueto, A., Barnes, P.J., Fabbri, L.M., Martinez, F.J., and Nishimura, M. (2013). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 187, 347-365.   DOI