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BMC Pulmonary Medicine
Published in: BMC Pulmonary Medicine 1/2017

Open Access 01-12-2017 | Research article

Gene expression analysis in asthma using a targeted multiplex array

Authors: Christopher D. Pascoe, Ma’en Obeidat, Bryna A. Arsenault, Yunlong Nie, Stephanie Warner, Dorota Stefanowicz, Samuel J. Wadsworth, Jeremy A. Hirota, S. Jasemine Yang, Delbert R. Dorscheid, Chris Carlsten, Tillie L. Hackett, Chun Y. Seow, Peter D. Paré

Published in: BMC Pulmonary Medicine | Issue 1/2017

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Abstract

Background

Gene expression changes in the structural cells of the airways are thought to play a role in the development of asthma and airway hyperresponsiveness. This includes changes to smooth muscle contractile machinery and epithelial barrier integrity genes. We used a targeted gene expression arrays to identify changes in the expression and co-expression of genes important in asthma pathology.

Methods

RNA was isolated from the airways of donor lungs from 12 patients with asthma (8 fatal) and 12 non-asthmatics controls and analyzed using a multiplexed, hypothesis-directed platform to detect differences in gene expression. Genes were grouped according to their role in airway dysfunction: airway smooth muscle contraction, cytoskeleton structure and regulation, epithelial barrier function, innate and adaptive immunity, fibrosis and remodeling, and epigenetics.

Results

Differential gene expression and gene co-expression analyses were used to identify disease associated changes in the airways of asthmatics. There was significantly decreased abundance of integrin beta 6 and Ras-Related C3 Botulinum Toxin Substrate 1 (RAC1) in the airways of asthmatics, genes which are known to play an important role in barrier function. Significantly elevated levels of Collagen Type 1 Alpha 1 (COL1A1) and COL3A1 which have been shown to modulate cell proliferation and inflammation, were found in asthmatic airways. Additionally, we identified patterns of differentially co-expressed genes related to pathways involved in virus recognition and regulation of interferon production. 7 of 8 pairs of differentially co-expressed genes were found to contain CCCTC-binding factor (CTCF) motifs in their upstream promoters.

Conclusions

Changes in the abundance of genes involved in cell-cell and cell-matrix interactions could play an important role in regulating inflammation and remodeling in asthma. Additionally, our results suggest that alterations to the binding site of the transcriptional regulator CTCF could drive changes in gene expression in asthmatic airways. Several asthma susceptibility loci are known to contain CTCF motifs and so understanding the role of this transcription factor may expand our understanding of asthma pathophysiology and therapeutic options.
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Literature
1.
James AL, Elliot JG, Jones RL, Carroll ML, Mauad T, Bai TR, et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med. 2012;185:1058–64.CrossRefPubMed
2.
3.
Holgate ST, Holloway J, Wilson S, Bucchieri F, Puddicombe S, Davies DE. Epithelial–Mesenchymal communication in the pathogenesis of chronic asthma. Proc Am Thorac Soc. 2004;1:93–8.CrossRefPubMed
4.
Tulah AS, Holloway JW, Sayers I. Defining the contribution of SNPs identified in asthma GWAS to clinical variables in asthmatic children. BMC Med Genet. 2013;14:100.CrossRefPubMedPubMedCentral
5.
Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, et al. Meta-analysis of genome-wide association studies of asthma in ethnically diverse north American populations. Nat Genet. 2011;43:887–92.CrossRefPubMedPubMedCentral
6.
van Eerdewegh P, Little RD, Dupuis J, del Mastro RG, Falls K, Simon J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002;418:426.CrossRefPubMed
7.
Hao K, Bosse Y, Nickle DC, Pare PD, Postma DS, Laviolette M, et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 2012;8:e1003029.CrossRefPubMedPubMedCentral
8.
Veldman-Jones MH, Brant R, Rooney C, Geh C, Emery H, Harbron CG, et al. Evaluating robustness and sensitivity of the NanoString technologies nCounter platform to enable multiplexed gene expression analysis of clinical samples. Cancer Res. 2015;75:2587–93.CrossRefPubMed
9.
Chin LY, Bosse Y, Pascoe CD, Hackett TL, Seow CY, Pare PD. Mechanical properties of asthmatic airway smooth muscle. Eur Respir J. 2012;40:45–54.CrossRefPubMed
10.
Hackett T-L, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, et al. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med. 2009;180:122–33.CrossRefPubMed
11.
Hirota JA, Hirota SA, Warner SM, Stefanowicz D, Shaheen F, Beck PL, et al. The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter. J Allergy Clin Immunol. 2012;129:1116–25. e6CrossRefPubMed
12.
Woodruff PG, Dolganov GM, Ferrando RE, Donnelly S, Hays SR, Solberg OD, et al. Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. Am J Respir Crit Care Med. 2004;169:1001–6.CrossRefPubMed
13.
Sieck GC, White TA, Thompson MA, Pabelick CM, Wylam ME, Prakash YS. Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle. Am J Physiol - Lung Cell Mol Physiol. 2008;294:L378–85.CrossRefPubMed
14.
Gunst SJ, Zhang W. Actin cytoskeletal dynamics in smooth muscle: a new paradigm for the regulation of smooth muscle contraction. Am J Physiol - Cell Physiol. 2008;295:C576–87.CrossRefPubMedPubMedCentral
15.
16.
Allahverdian S, Harada N, Singhera GK, Knight DA, Dorscheid DR. Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF. Am J Respir Cell Mol Biol. 2008;38:153–60.CrossRefPubMed
17.
Dorscheid DR, Wojcik KR, Yule K, White SR. Role of cell surface glycosylation in mediating repair of human airway epithelial cell monolayers. Am J Physiol Lung Cell Mol Physiol. 2001;281:L982–92.PubMed
18.
Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010;363:1211–21.CrossRefPubMedPubMedCentral
19.
Xu J, Singhera GK, Dorscheid DR. Expression of surfactant protein D in airways of asthmatics and interleukin-13 modulation of surfactant protein D in human models of airway epithelium. Respir Res. 2015;16:26.CrossRefPubMedPubMedCentral
20.
Hirota JA, Gold MJ, Hiebert PR, Parkinson LG, Wee T, Smith D, et al. The nucleotide-binding domain, leucine-rich repeat protein 3 inflammasome/IL-1 receptor I axis mediates innate, but not adaptive, immune responses after exposure to particulate matter under 10 μm. Am J Respir Cell Mol Biol. 2015;52:96–105.CrossRefPubMed
21.
Wang D-Z, Olson EN. Control of smooth muscle development by the myocardin family of transcriptional coactivators. Curr Opin Genet Dev. 2004;14:558.CrossRefPubMed
22.
Tsao P-N, Vasconcelos M, Izvolsky KI, Qian J, Lu J, Cardoso WV. Notch signaling controls the balance of ciliated and secretory cell fates in developing airways. Dev Camb Engl. 2009;136:2297–307.
23.
Kumagai K, Ohno I, Okada S, Ohkawara Y, Suzuki K, Shinya T, et al. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J Immunol Baltim Md 1950. 1999;162:4212–9.
24.
Stefanowicz D, Lee JY, Lee K, Shaheen F, Koo H-K, Booth S, et al. Elevated H3K18 acetylation in airway epithelial cells of asthmatic subjects. Respir Res. 2015;16:95.CrossRefPubMedPubMedCentral
25.
26.
Stefanowicz D, Hackett T-L, Garmaroudi FS, Günther OP, Neumann S, Sutanto EN, et al. DNA methylation profiles of airway epithelial cells and PBMCs from healthy, atopic and asthmatic children. PLoS One. 2012;7:e44213.CrossRefPubMedPubMedCentral
27.
Nyholt DR. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet. 2004;74:765–9.CrossRefPubMedPubMedCentral
28.
Li J, Ji L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity. 2005;95:221–7.CrossRefPubMed
29.
de Boer WI, Sharma HS, Baelemans SMI, Hoogsteden HC, Lambrecht BN, Braunstahl GJ. Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. Can J Physiol Pharmacol. 2008;86:105–12.CrossRefPubMed
30.
31.
Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, et al. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol. 1996;133:921–8.CrossRefPubMed
32.
Jolly L, Stavrou A, Vanderstoken G, Meliopoulos VA, Habgood A, Tatler AL, et al. Influenza promotes collagen deposition via αvβ6 Integrin-mediated transforming growth factor β activation. J Biol Chem. 2014;289:35246–63.CrossRefPubMedPubMedCentral
33.
Terakado M, Gon Y, Sekiyama A, Takeshita I, Kozu Y, Matsumoto K, et al. The Rac1/JNK pathway is critical for EGFR-dependent barrier formation in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2011;300:L56–63.CrossRefPubMed
34.
Jou T-S, Schneeberger EE, Nelson WJ. Structural and functional regulation of tight junctions by RhoA and Rac1 small GTPases. J Cell Biol. 1998;142:101–15.CrossRefPubMedPubMedCentral
35.
Hackett T-L. Epithelial-mesenchymal transition in the pathophysiology of airway remodelling in asthma. Curr Opin Allergy Clin Immunol. 2012;12:53–9.CrossRefPubMed
36.
37.
Liesker JJ, Hacken NHT, Zeinstra-Smith M, Rutgers SR, Postma DS, Timens W. Reticular basement membrane in asthma and COPD: similar thickness, yet different composition. Int J Chron Obstruct Pulmon Dis. 2009;4:127–35.PubMedPubMedCentral
38.
Chetta A, Foresi A, Del Donno M, Bertorelli G, Pesci A, Olivieri D. Airways remodeling is a distinctive feature of asthma and is related to severity of disease. Chest. 1997;111:852–7.CrossRefPubMed
39.
Wilson JW, Li X. The measurement of reticular basement membrane and submucosal collagen in the asthmatic airway. Clin Exp Allergy. 1997;27:363–71.CrossRefPubMed
40.
Setlakwe EL, Lemos KR, Lavoie-Lamoureux A, Duguay J-D, Lavoie J-P. Airway collagen and elastic fiber content correlates with lung function in equine heaves. Am J Physiol - Lung Cell Mol Physiol. 2014;307:L252–60.CrossRefPubMed
41.
Rogers NK, Clements D, Dongre A, Harrison TW, Shaw D, Johnson SR. Extra-cellular matrix proteins induce matrix Metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma. PLoS One. 2014;9:e90565.CrossRefPubMedPubMedCentral
42.
Dekkers BGJ, Spanjer AIR, van der Schuyt RD, Kuik WJ, Zaagsma J, Meurs H. Focal adhesion Kinase regulates collagen I–induced airway smooth muscle phenotype switching. J Pharmacol Exp Ther. 2013;346:86–95.CrossRefPubMed
43.
Chakir J, Shannon J, Molet S, Fukakusa M, Elias J, Laviolette M, et al. Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-β, IL-11, IL-17, and type I and type III collagen expression. J Allergy Clin Immunol. 2003;111:1293–8.CrossRefPubMed
44.
Bonacci JV, Schuliga M, Harris T, Stewart AG. Collagen impairs glucocorticoid actions in airway smooth muscle through integrin signalling. Br J Pharmacol. 2006;149:365–73.CrossRefPubMedPubMedCentral
45.
46.
Foley SC, Mogas AK, Olivenstein R, Fiset PO, Chakir J, Bourbeau J, et al. Increased expression of ADAM33 and ADAM8 with disease progression in asthma. J Allergy Clin Immunol. 2007;119:863–71.CrossRefPubMed
47.
Puxeddu I, Pang YY, Harvey A, Haitchi HM, Nicholas B, Yoshisue H, et al. The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: implications for airway remodeling in asthma. J Allergy Clin Immunol. 2008;121:1400–6. 1406.e1–4CrossRefPubMed
48.
49.
Garton KJ, Gough PJ, Blobel CP, Murphy G, Greaves DR, Dempsey PJ, et al. Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of Fractalkine (CX3CL1). J Biol Chem. 2001;276:37993–8001.PubMed
50.
Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, Miyado K, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998;17:7260–72.CrossRefPubMedPubMedCentral
51.
Jude JA, Dileepan M, Panettieri RA, Walseth TF, Kannan MS. Altered CD38/cyclic ADP-ribose Signaling contributes to the asthmatic phenotype. J Allergy. 2012;2012:289468.CrossRef
52.
Deshpande DA, White TA, Guedes AGP, Milla C, Walseth TF, Lund FE, et al. Altered airway responsiveness in CD38-deficient mice. Am J Respir Cell Mol Biol. 2005;32:149–56.CrossRefPubMed
53.
Myrtek D, Knoll M, Matthiesen T, Krause S, Lohrmann J, Schillinger D, et al. Expression of interleukin-13 receptor alpha 1-subunit on peripheral blood eosinophils is regulated by cytokines. Immunology. 2004;112:597–604.CrossRefPubMedPubMedCentral
54.
55.
56.
Parsons KS, Hsu AC, Wark PAB. TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection. Clin Exp Allergy J Br Soc Allergy Clin Immunol. 2014;44:91–101.CrossRef
57.
Wark PAB, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201:937–47.CrossRefPubMedPubMedCentral
58.
Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PAB, Bartlett NW, et al. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med. 2006;12:1023–6.CrossRefPubMed
59.
60.
de la Fuente A. From “differential expression” to “differential networking” – identification of dysfunctional regulatory networks in diseases. Trends Genet. 2010;26:326–33.CrossRefPubMed
61.
Ii M, Yamamoto H, Taniguchi H, Adachi Y, Nakazawa M, Ohashi H, et al. Co-expression of laminin β3 and γ2 chains and epigenetic inactivation of laminin α3 chain in gastric cancer. Int J Oncol. 2011;39:593–9.PubMed
62.
Porritt RA, Hertzog PJ. Dynamic control of type I IFN signalling by an integrated network of negative regulators. Trends Immunol. 2015;36:150–60.CrossRefPubMed
63.
64.
Mishiro T, Ishihara K, Hino S, Tsutsumi S, Aburatani H, Shirahige K, et al. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO J. 2009;28:1234–45.CrossRefPubMedPubMedCentral
65.
Verlaan DJ, Berlivet S, Hunninghake GM, Madore A-M, Larivière M, Moussette S, et al. Allele-specific chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet. 2009;85:377–93.CrossRefPubMedPubMedCentral
Metadata
Title
Gene expression analysis in asthma using a targeted multiplex array
Authors
Christopher D. Pascoe
Ma’en Obeidat
Bryna A. Arsenault
Yunlong Nie
Stephanie Warner
Dorota Stefanowicz
Samuel J. Wadsworth
Jeremy A. Hirota
S. Jasemine Yang
Delbert R. Dorscheid
Chris Carlsten
Tillie L. Hackett
Chun Y. Seow
Peter D. Paré
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2017
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-017-0545-9

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