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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2017

Open Access 01-12-2017 | Research article

Biosemantics guided gene expression profiling of Sjögren’s syndrome: a comparative analysis with systemic lupus erythematosus and rheumatoid arthritis

Authors: Nirav R. Shah, Braxton D. Noll, Craig B. Stevens, Michael T. Brennan, Farah B. Mougeot, Jean-Luc C. Mougeot

Published in: Arthritis Research & Therapy | Issue 1/2017

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Abstract

Background

Sjögren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These autoimmune diseases mostly affect women. In this study, concept profile analysis (CPA) and gene expression meta-analysis were used to identify genes potentially involved in SS pathogenesis.

Methods

Human genes associated with SS, SLE, and RA were identified using the CPA tool, Anni 2.1. The differential mRNA expression of genes common to SS and SLE (SS-SLE) was determined in female peripheral blood mononuclear cells (PBMCs) using NCBI-GEO2R. Differentially expressed (DE) SS-SLE PBMC genes in common with the SS-SLE CPA-identified genes were analyzed for differential expression in salivary glands or synovial biopsies, and for genes common to SS and RA and SLE and RA, analyzing differential expression in salivary glands in SS, synovial fibroblasts in RA, and synovial fluid in SLE. Among common genes, DE genes found in salivary gland mRNA expression in patients with SS were used for gene enrichment and SS molecular network construction. Secondary analysis was performed to identify DE genes unique to the disease site tissues, by excluding PBMC and CPA common DE genes to complement the SS network.

Results

We identified 22 DE genes in salivary gland datasets in SS that have not previously been clearly associated with SS pathogenesis. Among these, higher levels of checkpoint kinase 1 (CHEK1), V-Ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), and lymphoid enhancer binding factor 1 (LEF1) were significantly correlated with higher matrix metalloproteinase 9 (MMP9) levels. Higher MMP9 levels have been implicated in degradation of salivary gland structural integrity, leading to hypo-salivation in patients with SS. Salivary gland mRNA expression of MMP9 and the expression of cytokine CXCL10 were higher in patients with SS. CXCL10 has been shown to increase MMP9 expression and therefore may also play an important role in SS pathogenesis.

Conclusion

Using CPA and gene expression analysis, we identified factors targeting MMP9 expression and/or function, namely CHEK1, CXCL10, ETS1, LEF1, and tissue inhibitor of metalloproteinase 1; altered mRNA expression of these could increase expression/activity of MMP9 in a concerted manner, thereby potentially impacting SS pathogenesis.
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Literature
1.
Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology. 2006;45 Suppl 3:iii3–4.PubMed
2.
Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, Kelly JA, Dozmorov MG, Miceli-Richard C, Bowman S, et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome. Nat Genet. 2013;45(11):1284–92.CrossRefPubMed
3.
Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet. 2009;10(1):43–55.CrossRefPubMed
4.
Huizinga TW, Grondal G. Shared symptoms in rheumatic diseases: a blessing or a curse? Arthritis Rheum. 2009;60(9):2547–9.CrossRefPubMed
5.
6.
7.
Soto ME, Vallejo M, Guillen F, Simon JA, Arena E, Reyes PA. Gender impact in systemic lupus erythematosus. Clin Exp Rheumatol. 2004;22(6):713–21.PubMed
8.
Petri M. Musculoskeletal complications of systemic lupus erythematosus in the Hopkins Lupus Cohort: an update. Arthritis Care Res. 1995;8(3):137–45.CrossRefPubMed
9.
10.
Fairweather D, Petri MA, Coronado MJ, Cooper LT. Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis. Expert Rev Clin Immunol. 2012;8(3):269–84.CrossRefPubMedPubMedCentral
11.
Toro-Dominguez D, Carmona-Saez P, Alarcon-Riquelme ME. Shared signatures between rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome uncovered through gene expression meta-analysis. Arthritis Res Ther. 2014;16(6):489.CrossRefPubMedPubMedCentral
12.
Wang L, Wu LF, Lu X, Mo XB, Tang ZX, Lei SF, Deng FY. Integrated analyses of gene expression profiles digs out common markers for rheumatic diseases. PLoS One. 2015;10(9):e0137522.CrossRefPubMedPubMedCentral
13.
Song GG, Kim JH, Seo YH, Choi SJ, Ji JD, Lee YH. Meta-analysis of differentially expressed genes in primary Sjogren's syndrome by using microarray. Hum Immunol. 2014;75(1):98–104.CrossRefPubMed
14.
Yao Y, Liu Z, Jallal B, Shen N, Ronnblom L. Type I interferons in Sjogren's syndrome. Autoimmun Rev. 2013;12(5):558–66.CrossRefPubMed
15.
Brkic Z, Versnel MA. Type I IFN signature in primary Sjogren's syndrome patients. Expert Rev Clin Immunol. 2014;10(4):457–67.CrossRefPubMed
16.
Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z, Li P, Zhang L, Du Y, Luan H, et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren's syndrome at 7q11.23. Nat Genet. 2013;45(11):1361–5.CrossRefPubMed
17.
18.
Nandula SR, Dey P, Corbin KL, Nunemaker CS, Bagavant H, Deshmukh US. Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling. J Oral Pathol Med. 2013;42(1):66–72.CrossRefPubMed
19.
20.
Liu K, Kurien BT, Zimmerman SL, Kaufman KM, Taft DH, Kottyan LC, Lazaro S, Weaver CA, Ice JA, Adler AJ, et al. X Chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47, XXX in systemic lupus erythematosus and Sjogren's syndrome. Arthritis Rheumatol. 2016;68(5):1290–300.PubMedPubMedCentral
21.
Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune WJ, Somers E, Gonzalez-Rivera T, Michigan Lupus C, Strickland F, Richardson B. Overexpression of X-linked genes in T cells from women with lupus. J Autoimmun. 2013;41:60–71.CrossRefPubMedPubMedCentral
22.
Lu Q, Wu A, Tesmer L, Ray D, Yousif N, Richardson B. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol. 2007;179(9):6352–8.CrossRefPubMed
23.
Perl A. Role of endogenous retroviruses in autoimmune diseases. Rheum Dis Clin N Am. 2003;29(1):123–43. vii.CrossRef
24.
Perl A. Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren's syndrome. Curr Opin Rheumatol. 2009;21(5):443–7.CrossRefPubMedPubMedCentral
25.
Brennan MT, Mougeot JL. Alu retroelement-associated autoimmunity in Sjogren's syndrome. Oral Dis. 2016;22(5):345–7.CrossRefPubMed
26.
Jelier R, Schuemie MJ, Roes PJ, van Mulligen EM, Kors JA. Literature-based concept profiles for gene annotation: the issue of weighting. Int J Med Inform. 2008;77(5):354–62.CrossRefPubMed
27.
Hettne KM, Dharuri H, Zhao J, Wolstencroft K, Belhajjame K, Soiland-Reyes S, Mina E, Thompson M, Cruickshank D, Verdes-Montenegro L, et al. Structuring research methods and data with the research object model: genomics workflows as a case study. J Biomed Semant. 2014;5(1):41.CrossRef
28.
Hettne KM, Weeber M, Laine ML, ten Cate H, Boyer S, Kors JA, Loos BG. Automatic mining of the literature to generate new hypotheses for the possible link between periodontitis and atherosclerosis: lipopolysaccharide as a case study. J Clin Periodontol. 2007;34(12):1016–24.CrossRefPubMed
29.
30.
Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, et al. NCBI GEO: archive for functional genomics data sets − update. Nucleic Acids Res. 2013;41(Database issue):D991–995.CrossRefPubMed
31.
Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, Vilo J. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 2016;44(W1):W83–89.CrossRefPubMedPubMedCentral
32.
Greenwell-Wild T, Moutsopoulos NM, Gliozzi M, Kapsogeorgou E, Rangel Z, Munson PJ, Moutsopoulos HM, Wahl SM. Chitinases in the salivary glands and circulation of patients with Sjogren's syndrome: macrophage harbingers of disease severity. Arthritis Rheum. 2011;63(10):3103–15.CrossRefPubMedPubMedCentral
33.
Tsuboi H, Nakai Y, Iizuka M, Asashima H, Hagiya C, Tsuzuki S, Hirota T, Miki H, Hagiwara S, Kondo Y, et al. DNA microarray analysis of labial salivary glands in IgG4-related disease: comparison with Sjogren's syndrome. Arthritis Rheumatol. 2014;66(10):2892–9.CrossRefPubMed
34.
Horvath S, Nazmul-Hossain AN, Pollard RP, Kroese FG, Vissink A, Kallenberg CG, Spijkervet FK, Bootsma H, Michie SA, Gorr SU, et al. Systems analysis of primary Sjogren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model. Arthritis Res Ther. 2012;14(6):R238.CrossRefPubMedPubMedCentral
35.
Tabas-Madrid D, Nogales-Cadenas R, Pascual-Montano A. GeneCodis3: a non-redundant and modular enrichment analysis tool for functional genomics. Nucleic Acids Res. 2012;40(Web Server issue):W478–483.
36.
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–452.CrossRefPubMed
37.
Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjogren's syndrome. Nat Rev Rheumatol. 2010;6(9):529–37.CrossRefPubMed
38.
Szabo K, Papp G, Dezso B, Zeher M. The histopathology of labial salivary glands in primary Sjogren's syndrome: focusing on follicular helper T cells in the inflammatory infiltrates. Mediat Inflamm. 2014;2014:631787.CrossRef
39.
Gabba A, Piga M, Vacca A, Porru G, Garau P, Cauli A, Mathieu A. Joint and tendon involvement in systemic lupus erythematosus: an ultrasound study of hands and wrists in 108 patients. Rheumatology. 2012;51(12):2278–85.CrossRefPubMed
40.
Perez P, Kwon YJ, Alliende C, Leyton L, Aguilera S, Molina C, Labra C, Julio M, Leyton C, Gonzalez MJ. Increased acinar damage of salivary glands of patients with Sjogren's syndrome is paralleled by simultaneous imbalance of matrix metalloproteinase 3/tissue inhibitor of metalloproteinases 1 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 ratios. Arthritis Rheum. 2005;52(9):2751–60.CrossRefPubMed
41.
Asatsuma M, Ito S, Watanabe M, Takeishi H, Nomura S, Wada Y, Nakano M, Gejyo F, Igarashi A. Increase in the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 in saliva from patients with primary Sjogren's syndrome. Clin Chim Acta. 2004;345(1-2):99–104.CrossRefPubMed
42.
Nogales-Cadenas R, Carmona-Saez P, Vazquez M, Vicente C, Yang X, Tirado F, Carazo JM, Pascual-Montano A. GeneCodis: interpreting gene lists through enrichment analysis and integration of diverse biological information. Nucleic Acids Res. 2009;37(Web Server issue):W317–22.
43.
Carmona-Saez P, Chagoyen M, Tirado F, Carazo JM, Pascual-Montano A. GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists. Genome Biol. 2007;8(1):R3.CrossRefPubMedPubMedCentral
44.
Ghosh S, Basu M, Roy SS. ETS-1 protein regulates vascular endothelial growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3. J Biol Chem. 2012;287(18):15001–15.CrossRefPubMedPubMedCentral
45.
Nakamura Y, Esnault S, Maeda T, Kelly EA, Malter JS, Jarjour NN. Ets-1 regulates TNF-alpha-induced matrix metalloproteinase-9 and tenascin expression in primary bronchial fibroblasts. J Immunol. 2004;172(3):1945–52.CrossRefPubMed
46.
Wang WJ, Yao Y, Jiang LL, Hu TH, Ma JQ, Liao ZJ, Yao JT, Li DF, Wang SH, Nan KJ. Knockdown of lymphoid enhancer factor 1 inhibits colon cancer progression in vitro and in vivo. PLoS One. 2013;8(10):e76596.CrossRefPubMedPubMedCentral
47.
Zipin-Roitman A, Meshel T, Sagi-Assif O, Shalmon B, Avivi C, Pfeffer RM, Witz IP, Ben-Baruch A. CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. Cancer Res. 2007;67(7):3396–405.CrossRefPubMed
48.
Nzeusseu Toukap A, Galant C, Theate I, Maudoux AL, Lories RJ, Houssiau FA, Lauwerys BR. Identification of distinct gene expression profiles in the synovium of patients with systemic lupus erythematosus. Arthritis Rheum. 2007;56(5):1579–88.CrossRefPubMed
49.
Woetzel D, Huber R, Kupfer P, Pohlers D, Pfaff M, Driesch D, Haupl T, Koczan D, Stiehl P, Guthke R, et al. Identification of rheumatoid arthritis and osteoarthritis patients by transcriptome-based rule set generation. Arthritis Res Ther. 2014;16(2):R84.CrossRefPubMedPubMedCentral
50.
Subramanian A, Tamayoa P, Moothaa VK, Mukherjeed S, Eberta BL, Gillettea MA, Paulovich A, Scott L, Pomeroyh SL, Goluba TR, Landera ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. PNAS. 2005;102(43):15545–50.CrossRefPubMedPubMedCentral
51.
Markey GM. Carboxylesterase 1 (Ces1): from monocyte marker to major player. J Clin Pathol. 2011;64(2):107–9.CrossRefPubMed
52.
Royer B, Cazals-Hatem D, Sibilia J, Agbalika F, Cayuela JM, Soussi T, Maloisel F, Clauvel JP, Brouet JC, Mariette X. Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood. 1997;90(2):766–75.PubMed
53.
Goicovich E, Molina C, Perez P, Aguilera S, Fernandez J, Olea N, Alliende C, Leyton C, Romo R, Leyton L, et al. Enhanced degradation of proteins of the basal lamina and stroma by matrix metalloproteinases from the salivary glands of Sjogren's syndrome patients: correlation with reduced structural integrity of acini and ducts. Arthritis Rheum. 2003;48(9):2573–84.CrossRefPubMed
54.
Crampton SP, Wu B, Park EJ, Kim JH, Solomon C, Waterman ML, Hughes CC. Integration of the beta-catenin-dependent Wnt pathway with integrin signaling through the adaptor molecule Grb2. PLoS One. 2009;4(11):e7841.CrossRefPubMedPubMedCentral
55.
Xu J, Li Y, Wang F, Wang X, Cheng B, Ye F, Xie X, Zhou C, Lu W. Suppressed miR-424 expression via upregulation of target gene Chk1 contributes to the progression of cervical cancer. Oncogene. 2013;32(8):976–87.CrossRefPubMed
56.
Vempati P, Karagiannis ED, Popel AS. A biochemical model of matrix metalloproteinase 9 activation and inhibition. J Biol Chem. 2007;282(52):37585–96.CrossRefPubMed
57.
Shin SY, Nam JS, Lim Y, Lee YH. TNFalpha-exposed bone marrow-derived mesenchymal stem cells promote locomotion of MDA-MB-231 breast cancer cells through transcriptional activation of CXCR3 ligand chemokines. J Biol Chem. 2010;285(40):30731–40.CrossRefPubMedPubMedCentral
58.
Carneiro T, Khair L, Reis CC, Borges V, Moser BA, Nakamura TM, Ferreira MG. Telomeres avoid end detection by severing the checkpoint signal transduction pathway. Nature. 2010;467(7312):228–32.CrossRefPubMedPubMedCentral
59.
Wei C, Skopp R, Takata M, Takeda S, Price CM. Effects of double-strand break repair proteins on vertebrate telomere structure. Nucleic Acids Res. 2002;30(13):2862–70.CrossRefPubMedPubMedCentral
60.
61.
Schoeftner S, Blanco R, Lopez de Silanes I, Munoz P, Gomez-Lopez G, Flores JM, Blasco MA. Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations. Proc Natl Acad Sci U S A. 2009;106(46):19393–8.CrossRefPubMedPubMedCentral
62.
63.
64.
65.
Weeber M, Klein H, Aronson AR, Mork JG, de Jong-van den Berg LT, Vos R. Text-based discovery in biomedicine: the architecture of the DAD-system. Proc AMIA Symp. 2000:903-907.
Metadata
Title
Biosemantics guided gene expression profiling of Sjögren’s syndrome: a comparative analysis with systemic lupus erythematosus and rheumatoid arthritis
Authors
Nirav R. Shah
Braxton D. Noll
Craig B. Stevens
Michael T. Brennan
Farah B. Mougeot
Jean-Luc C. Mougeot
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-017-1400-3

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