Advertisement

SAMD9 is a (epi-) genetically regulated anti-inflammatory factor activated in RA patients

  • Pei He
  • Long-Fei Wu
  • Peng-Fei Bing
  • Wei Xia
  • Lan Wang
  • Fang-Fei Xie
  • Xin Lu
  • Shu-Feng Lei
  • Fei-Yan DengEmail author
Article
  • 27 Downloads

Abstract

To identify PBMC-expressed genes significant for RA, and to ascertain their upstream regulatory factors, as well as downstream functional effects relevant to RA pathogenesis. We performed peripheral blood mononuclear cells (PBMCs) transcriptome-wide mRNA expression profiling in a case–control discovery sample. Differentially expressed genes (DEGs) were identified and validated in PBMCs in independent samples. We also generated genome-wide SNP genotyping data, and collected miRNA expression data and DNA methylation data from PBMCs of the discovery sample. Pearson correlation analyses were conducted to identify miRNAs/DNA methylations influencing DEG expression. Association analyses were conducted to identify expression-regulating SNPs. The key DEG, SAMD9, which was reported to function as a tumor suppressor gene, was assessed for its effects on T cell proliferation, apoptosis, and inflammatory cytokine expression. A total of 181 DEGs (Fold Change ≥ 2.0, Bonferroni adjusted p ≤ 0.05) were discovered in PBMCs. Four DEGs (SAMD9, CKLF, PARP9, and GUSB), upregulated with RA, were validated independently in PBMCs. Specifically, SAMD9 mRNA expression level was significantly upregulated in PHA-activated Jurkat T cells in vitro, and correlated with 8 miRNAs and associated with 22 SNPs in PBMCs in vivo. Knockdown of SAMD9 could transiently promote Jurkat T cell proliferation within 48 h and significantly induce TNF-α and IL-8 expression in T cells. SAMD9 expression is (epi-) genetically regulated, and significantly upregulated in PBMCs in RA patients and in activated T cells in vitro. SAMD9 might serve as a T cell activation marker but act as an anti-inflammatory factor.

Keywords

Rheumatoid arthritis PBMCs SAMD9 Epigenetic factor 

Notes

Acknowledgements

The study was supported by Natural Science Foundation of China (81373010, 81473046, 81541068, 31271336, 81502868, 31401079 and 81401343), the Natural Science Foundation of Jiangsu Province (BK20150346), the Startup Fund from Soochow University (Q413900112, Q413900712) and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Institutional Research Ethic Board at the Soochow University (ethics approval number: 2012-146). All the participants signed informed consent form.

Supplementary material

11010_2019_3499_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 438 KB)

References

  1. 1.
    MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, Silman AJ (2000) Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43:30–37CrossRefPubMedGoogle Scholar
  2. 2.
    Tedeschi SK, Bermas B, Costenbader KH (2013) Sexual disparities in the incidence and course of SLE and RA. Clin Immunol 149:211–218CrossRefPubMedGoogle Scholar
  3. 3.
    Biswas S, Manikandan J, Pushparaj PN (2011) Decoding the differential biomarkers of Rheumatoid arthritis and Osteoarthritis: a functional genomics paradigm to design disease specific therapeutics. Bioinformation 6:153–157CrossRefPubMedGoogle Scholar
  4. 4.
    van der Linden MP, Feitsma AL, le Cessie S, Kern M, Olsson LM, Raychaudhuri S, Begovich AB, Chang M, Catanese JJ, Kurreeman FA, van Nies J, van der Heijde DM, Gregersen PK, Huizinga TW, Toes RE, van der Helm-Van Mil AH (2009) Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis. Arthritis Rheum 60:2242–2247CrossRefPubMedGoogle Scholar
  5. 5.
    (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678.  https://doi.org/10.1038/nature05911
  6. 6.
    Morgan AW, Robinson JI, Conaghan PG, Martin SG, Hensor EM, Morgan MD, Steiner L, Erlich HA, Gooi HC, Barton A, Worthington J, Emery P (2010) Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort. Arthritis Res Ther 12:30CrossRefGoogle Scholar
  7. 7.
    Maseda D, Bonami RH, Crofford LJ (2014) Regulation of B lymphocytes and plasma cells by innate immune mechanisms and stromal cells in rheumatoid arthritis. Expert Rev Clin Immunol 10:747–762.  https://doi.org/10.1586/1744666x.2014.907744 CrossRefPubMedGoogle Scholar
  8. 8.
    Chowdhury K, Kumar U, Das S, Chaudhuri J, Kumar P, Kanjilal M, Ghosh P, Sircar G, Basyal RK, Kanga U, Bandyopadhaya S, Mitra DK (2018) Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis. Arthritis Res Ther 20:017–1505CrossRefGoogle Scholar
  9. 9.
    Kurowska W, Kuca-Warnawin E, Radzikowska A, Jakubaszek M, Maslinska M, Kwiatkowska B, Maslinski W (2018) Monocyte-related biomarkers of rheumatoid arthritis development in undifferentiated arthritis patients - a pilot study. Reumatologia 56:10–16.  https://doi.org/10.5114/reum.2018.74742 CrossRefPubMedGoogle Scholar
  10. 10.
    Ishigaki K, Shoda H, Kochi Y, Yasui T, Kadono Y, Tanaka S, Fujio K, Yamamoto K (2015) Quantitative and qualitative characterization of expanded CD4 + T cell clones in rheumatoid arthritis patients. Sci Rep 5:12937.  https://doi.org/10.1038/srep12937 CrossRefPubMedGoogle Scholar
  11. 11.
    Bui VL, Brahn E (2018) Cytokine targeting in rheumatoid arthritis. Clin Immunol.  https://doi.org/10.1016/j.clim.2018.04.001 PubMedGoogle Scholar
  12. 12.
    Paludan SR (2000) Synergistic action of pro-inflammatory agents: cellular and molecular aspects. J Leukoc Biol 67:18–25CrossRefPubMedGoogle Scholar
  13. 13.
    Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20:350–358CrossRefPubMedGoogle Scholar
  14. 14.
    Grabiec AM, Reedquist KA (2013) The ascent of acetylation in the epigenetics of rheumatoid arthritis. Nat Rev Rheumatol 9(5):311–318.  https://doi.org/10.1038/nrrheum.2013.17 CrossRefPubMedGoogle Scholar
  15. 15.
    Ehrlich M, Lacey M (2013) DNA methylation and differentiation: silencing, upregulation and modulation of gene expression. Epigenomics 5:553–568.  https://doi.org/10.2217/epi.13.43 CrossRefPubMedGoogle Scholar
  16. 16.
    Xiao C, Rajewsky K (2009) MicroRNA control in the immune system: basic principles. Cell 136:26–36CrossRefPubMedGoogle Scholar
  17. 17.
    Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X, Li J, Zhou H, Tang Y, Shen N (2010) MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4 + T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 184:6773–6781CrossRefPubMedGoogle Scholar
  18. 18.
    Klein K, Gay S (2015) Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol 27:76–82.  https://doi.org/10.1097/bor.0000000000000128 CrossRefPubMedGoogle Scholar
  19. 19.
    He P, Xia W, Wang L, Wu J, Guo YF, Zeng KQ, Wang MJ, Bing PF, Xie FF, Lu X, Zhang YH, Lei SF, Deng FY (2018) Identification of expression quantitative trait loci (eQTLs) in human peripheral blood mononuclear cells (PBMCs) and shared with liver and brain. J Cell Biochem 119:1659–1669CrossRefPubMedGoogle Scholar
  20. 20.
    Goeman JJ, Solari A (2014) Multiple hypothesis testing in genomics. Stat Med 33:1946–1978CrossRefPubMedGoogle Scholar
  21. 21.
    Zhao H, Nyholt DR, Yang Y, Wang J, Yang Y (2017) Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from linkage disequilibrium blocks. Sci Rep 7:3512.  https://doi.org/10.1038/s41598-017-03826-2 CrossRefPubMedGoogle Scholar
  22. 22.
    Wong N, Wang X (2015) miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res 43:5CrossRefGoogle Scholar
  23. 23.
    Dweep H, Sticht C, Pandey P, Gretz N (2011) miRWalk–database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Inform 44:839–847CrossRefPubMedGoogle Scholar
  24. 24.
    Wang L, Zhu J, Deng FY, Wu LF, Mo XB, Zhu XW, Xia W, Xie FF, He P, Bing PF, Qiu YH, Lin X, Lu X, Zhang L, Yi NJ, Zhang YH, Lei SF (2018) Correlation analyses revealed global microRNA-mRNA expression associations in human peripheral blood mononuclear cells. Mol Genet Genomics 293:95–105CrossRefPubMedGoogle Scholar
  25. 25.
    Xie FF, Deng FY, Wu LF, Mo XB, Zhu H, Wu J, Guo YF, Zeng KQ, Wang MJ, Zhu XW, Xia W, Wang L, He P, Bing PF, Lu X, Zhang YH, Lei SF (2018) Multiple correlation analyses revealed complex relationship between DNA methylation and mRNA expression in human peripheral blood mononuclear cells. Funct Integr Genomics 18:1–10.  https://doi.org/10.1007/s10142-017-0568-6 CrossRefPubMedGoogle Scholar
  26. 26.
    Jouy F, Muller SA, Wagner J, Otto W, von Bergen M, Tomm JM (2015) Integration of conventional quantitative and phospho-proteomics reveals new elements in activated Jurkat T-cell receptor pathway maintenance. Proteomics 15:25–33.  https://doi.org/10.1002/pmic.201400119 CrossRefPubMedGoogle Scholar
  27. 27.
    Lin YP, Su CC, Huang JY, Lin HC, Cheng YJ, Liu MF, Yang BC (2009) Aberrant integrin activation induces p38 MAPK phosphorylation resulting in suppressed Fas-mediated apoptosis in T cells: implications for rheumatoid arthritis. Mol Immunol 46:3328–3335.  https://doi.org/10.1016/j.molimm.2009.07.021 CrossRefPubMedGoogle Scholar
  28. 28.
    Lee EY, Seo M, Juhnn YS, Kim JY, Hong YJ, Lee YJ, Lee EB, Song YW (2011) Potential role and mechanism of IFN-gamma inducible protein-10 on receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rheumatoid arthritis. Arthritis Res Ther 13:R104.  https://doi.org/10.1186/ar3385 CrossRefPubMedGoogle Scholar
  29. 29.
    Li T, Zhong J, Chen Y, Qiu X, Zhang T, Ma D, Han W (2006) Expression of chemokine-like factor 1 is upregulated during T lymphocyte activation. Life Sci 79:519–524CrossRefPubMedGoogle Scholar
  30. 30.
    Bramwell KK, Ma Y, Weis JH, Chen X, Zachary JF, Teuscher C, Weis JJ (2014) Lysosomal beta-glucuronidase regulates Lyme and rheumatoid arthritis severity. J Clin Invest 124:311–320CrossRefPubMedGoogle Scholar
  31. 31.
    Zhu H, Wu LF, Mo XB, Lu X, Tang H, Zhu XW, Xia W, Guo YF, Wang MJ, Zeng KQ, Wu J, Qiu YH, Lin X, Zhang YH, Liu YZ, Yi NJ, Deng FY, Lei SF (2019) Rheumatoid arthritis-associated DNA methylation sites in peripheral blood mononuclear cells. Ann Rheum Dis 78:36–42.  https://doi.org/10.1136/annrheumdis-2018-213970 CrossRefPubMedGoogle Scholar
  32. 32.
    Lemos de Matos A, Liu J, McFadden G, Esteves PJ (2013) Evolution and divergence of the mammalian SAMD9/SAMD9L gene family. BMC Evol Biol 13:1471–2148CrossRefGoogle Scholar
  33. 33.
    Tanaka M, Shimbo T, Kikuchi Y, Matsuda M, Kaneda Y (2010) Sterile alpha motif containing domain 9 is involved in death signaling of malignant glioma treated with inactivated Sendai virus particle (HVJ-E) or type I interferon. Int J Cancer 126:1982–1991.  https://doi.org/10.1002/ijc.24965 CrossRefPubMedGoogle Scholar
  34. 34.
    Topaz O, Indelman M, Chefetz I, Geiger D, Metzker A, Altschuler Y, Choder M, Bercovich D, Uitto J, Bergman R, Richard G, Sprecher E (2006) A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet 79:759–764CrossRefPubMedGoogle Scholar
  35. 35.
    Bodolay E, Koch AE, Kim J, Szegedi G, Szekanecz Z (2002) Angiogenesis and chemokines in rheumatoid arthritis and other systemic inflammatory rheumatic diseases. J Cell Mol Med 6:357–376CrossRefPubMedGoogle Scholar
  36. 36.
    Szekanecz Z, Vegvari A, Szabo Z, Koch AE (2010) Chemokines and chemokine receptors in arthritis. Front Biosci 2:153–167CrossRefGoogle Scholar
  37. 37.
    Mateen S, Zafar A, Moin S, Khan AQ, Zubair S (2016) Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta 455:161–171CrossRefPubMedGoogle Scholar
  38. 38.
    Juarranz MG, Santiago B, Torroba M, Gutierrez-Canas I, Palao G, Galindo M, Abad C, Martinez C, Leceta J, Pablos JL, Gomariz RP (2004) Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells. Rheumatology 43:416–422.  https://doi.org/10.1093/rheumatology/keh061 CrossRefPubMedGoogle Scholar
  39. 39.
    Chefetz I, Ben Amitai D, Browning S, Skorecki K, Adir N, Thomas MG, Kogleck L, Topaz O, Indelman M, Uitto J, Richard G, Bradman N, Sprecher E (2008) Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-alpha responsive protein. J Invest Dermatol 128:1423–1429CrossRefPubMedGoogle Scholar
  40. 40.
    Li CF, MacDonald JR, Wei RY, Ray J, Lau K, Kandel C, Koffman R, Bell S, Scherer SW, Alman BA (2007) Human sterile alpha motif domain 9, a novel gene identified as down-regulated in aggressive fibromatosis, is absent in the mouse. BMC Genomics 8:1471–2164Google Scholar
  41. 41.
    Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C, Ingle CE, Dunning M, Flicek P, Koller D, Montgomery S, Tavare S, Deloukas P, Dermitzakis ET (2007) Population genomics of human gene expression. Nat Genet 39:1217–1224CrossRefPubMedGoogle Scholar
  42. 42.
    van Baarsen LG, Wijbrandts CA, Rustenburg F, Cantaert T, van der Pouw Kraan TC, Baeten DL, Dijkmans BA, Tak PP, Verweij CL (2010) Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther 12:22CrossRefGoogle Scholar
  43. 43.
    Sanda C, Weitzel P, Tsukahara T, Schaley J, Edenberg HJ, Stephens MA, McClintick JN, Blatt LM, Li L, Brodsky L, Taylor MW (2006) Differential gene induction by type I and type II interferons and their combination. J Interferon Cytokine Res 26:462–472CrossRefPubMedGoogle Scholar
  44. 44.
    Hershkovitz D, Gross Y, Nahum S, Yehezkel S, Sarig O, Uitto J, Sprecher E (2011) Functional characterization of SAMD9, a protein deficient in normophosphatemic familial tumoral calcinosis. J Invest Dermatol 131:662–669CrossRefPubMedGoogle Scholar
  45. 45.
    Mekhedov SL, Makarova KS, Koonin EV (2017) The complex domain architecture of SAMD9 family proteins, predicted STAND-like NTPases, suggests new links to inflammation and apoptosis. Biol Direct 12:017–0185CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Pei He
    • 1
    • 2
  • Long-Fei Wu
    • 1
    • 2
  • Peng-Fei Bing
    • 1
    • 2
  • Wei Xia
    • 1
    • 2
  • Lan Wang
    • 1
    • 2
  • Fang-Fei Xie
    • 1
    • 2
  • Xin Lu
    • 1
    • 2
  • Shu-Feng Lei
    • 1
    • 2
  • Fei-Yan Deng
    • 1
    • 2
    Email author
  1. 1.Center for Genetic Epidemiology and Genomics, School of Public HealthMedical College of Soochow UniversitySuzhouPeople’s Republic of China
  2. 2.Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric DiseasesSoochow UniversitySuzhouPeople’s Republic of China

Personalised recommendations