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Epigenetics of Systemic Sclerosis

  • Nezam Altorok
  • Vivek Nagaraja
  • Bashar KahalehEmail author
Reference work entry

Abstract

Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by vascular dysfunction, activation of the immune system, and tissue fibrosis. SSc is associated with high mortality and morbidity. The precise etiology of SSc is undetermined, but there is evidence suggestive of a link between environmental factors and SSc pathogenesis. In this chapter, we will define and discuss the various clinical manifestations of SSc, and then we will review the evidence of environmental factor role in SSc. Next, we will evaluate the evidence for epigenetic regulation in SSc and the potential role of epigenetic aberrancies in SSc pathogenesis.

Keywords

Scleroderma Systemic sclerosis Epigenetics DNA methylation Histone modification MicroRNA Fibroblasts Fibrosis Microvascular endothelial cells Environment Silica 

List of Abbreviations

ACE inhibitors

Angiotensin converting enzyme inhibitors

ACTA

Actin, alpha 2, smooth muscle, aorta gene

ACR

American College of Rheumatology

BMPRII

Bone morphogenetic protein type II receptor

dcSSc

Diffuse cutaneous systemic sclerosis

DNMT1

DNA (cytosine-5-)-methyltransferase 1

ECM

Extracellular matrix

EMS

Eosinophilia-myalgia syndrome

FB

Fibroblasts

FLI1

Friend leukemia virus integration gene

GI

Gastrointestinal

H3K27me3

Trimethylation of histone H3 on lysine 27

lcSSc

Limited cutaneous systemic sclerosis

LSc

Localized scleroderma

MBD-1

Methyl-CpG-binding domain protein1

MCP

Metacarpal phalangeal joints

MeCP-2

Methyl-CpG-binding protein 2

MMP-1

Matrix metalloproteinase 1

MVEC

Microvascular endothelial cells

NFD

Nephrogenic fibrosing dermopathy

NOS

Nitric oxide synthase

NSF

Nephrogenic systemic fibrosis

PAH

Pulmonary arterial hypertension

PCE

Perchloroethylene

PVC

Polyvinyl chloride

RP

Raynaud’s phenomenon

SMAD

Intracellular proteins that transduce extracellular signals from TGF-β ligands

SRC

Scleroderma renal crisis

SSc

Systemic sclerosis

TCA

Trichloroethane

TEC

Trichloroethylene

TGF-β

Transforming growth factor-β

TOC

Toxic oil syndrome

VC

Vinyl chloride

References

  1. Abraham DJ, Varga J (2005) Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol 26(11):587–595CrossRefGoogle Scholar
  2. Allen JA, Peterson A, Sufit R, Hinchcliff ME, Mahoney JM, Wood TA, Miller FW, Whitfield ML, Varga J (2011) Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan. Arthritis Rheum 63(11):3633–3639CrossRefGoogle Scholar
  3. Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH (2014a) Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis 74(8):1612–1620Google Scholar
  4. Altorok N, Wang Y, Kahaleh B (2014b) Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol 26(6):615–620CrossRefGoogle Scholar
  5. Altorok N, Wang YQ, Kahaleh B (2014c) Endothelial dysfunction in systemic sclerosis. Curr Opin Rheumatol 26(6):615–620CrossRefGoogle Scholar
  6. Altorok N, Almeshal N, Wang Y, Kahaleh B (2015) Epigenetics, the holy grail in the pathogenesis of systemic sclerosis. Rheumatology (Oxford) 54(10):1759–1770CrossRefGoogle Scholar
  7. Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD (2001) Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum 44(6):1359–1362CrossRefGoogle Scholar
  8. Atfi A, Dumont E, Colland F, Bonnier D, L’Helgoualc’h A, Prunier C, Ferrand N, Clement B, Wewer UM, Theret N (2007) The disintegrin and metalloproteinase ADAM12 contributes to TGF-beta signaling through interaction with the type II receptor. J Cell Biol 178(2):201–208CrossRefGoogle Scholar
  9. Black CM, Welsh KI, Walker AE, Bernstein RM, Catoggio LJ, McGregor AR, Jones JK (1983) Genetic susceptibility to scleroderma-like syndrome induced by vinyl chloride. Lancet 1(8314–5):53–55CrossRefGoogle Scholar
  10. Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, Lin NY, Beyer C, Distler O, Schett G, Distler JH (2013) The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis 73(6):1232–1239Google Scholar
  11. Denoeud J, Moser M (2011) Role of CD27/CD70 pathway of activation in immunity and tolerance. J Leukoc Biol 89(2):195–203CrossRefGoogle Scholar
  12. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison CD, Chan KK, Marcucci G, Calin GA, Huebner K, Croce CM (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 104(40):15805–15810CrossRefGoogle Scholar
  13. Feghali-Bostwick C, Medsger TA Jr, Wright TM (2003) Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 48(7):1956–1963CrossRefGoogle Scholar
  14. Gabrielli A, Avvedimento EV, Krieg T (2009) Scleroderma. N Engl J Med 360(19):1989–2003CrossRefGoogle Scholar
  15. Galan A, Cowper SE, Bucala R (2006) Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy). Curr Opin Rheumatol 18(6):614–617CrossRefGoogle Scholar
  16. Gama C, Meira JBB (1978) Occupational acro-osteolysis. J Bone Jt Surg Am 60(1):86–90CrossRefGoogle Scholar
  17. Ghosh AK, Bhattacharyya S, Lafyatis R, Farina G, Yu J, Thimmapaya B, Wei J, Varga J (2013) p300 is elevated in systemic sclerosis and its expression is positively regulated by TGF-beta: epigenetic feed-forward amplification of fibrosis. J Invest Dermatol 133(5):1302–1310CrossRefGoogle Scholar
  18. Hertzman PA, Blevins WL, Mayer J, Greenfield B, Ting M, Gleich GJ (1990) Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 322(13):869–873CrossRefGoogle Scholar
  19. Jiang H, Xiao R, Lian X, Kanekura T, Luo Y, Yin Y, Zhang G, Yang Y, Wang Y, Zhao M, Lu Q (2012) Demethylation of TNFSF7 contributes to CD70 overexpression in CD4+ T cells from patients with systemic sclerosis. Clin Immunol 143(1):39–44CrossRefGoogle Scholar
  20. Kahaleh B, Wang W (2012) Decrease activity of DNA demethylase in SSC fibroblast and microvascular endothelial cells: a possible mechanism for persistent SSC phenotype [Abstract]. Rheumatology (Oxford) 51:ii5e6CrossRefGoogle Scholar
  21. Korn JH (2003) Scleroderma: a treatable disease. Cleve Clin J Med 70(11):954. 956, 958 passimCrossRefGoogle Scholar
  22. Kramer M, Dees C, Huang J, Schlottmann I, Palumbo-Zerr K, Zerr P, Gelse K, Beyer C, Distler A, Marquez VE, Distler O, Schett G, Distler JH (2013) Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis 72(4):614–620CrossRefGoogle Scholar
  23. Kriegel AJ, Liu Y, Fang Y, Ding X, Liang M (2012) The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol Genomics 44(4):237–244CrossRefGoogle Scholar
  24. Kubo M, Czuwara-Ladykowska J, Moussa O, Markiewicz M, Smith E, Silver RM, Jablonska S, Blaszczyk M, Watson DK, Trojanowska M (2003) Persistent down-regulation of Fli1, a suppressor of collagen transcription, in fibrotic scleroderma skin. Am J Pathol 163(2):571–581CrossRefGoogle Scholar
  25. Lei W, Luo Y, Lei W, Luo Y, Yan K, Zhao S, Li Y, Qiu X, Zhou Y, Long H, Zhao M, Liang Y, Su Y, Lu Q (2009) Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand J Rheumatol 38(5):369–374CrossRefGoogle Scholar
  26. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 15(2):202–205PubMedGoogle Scholar
  27. Li Q, Zhu H, Luo H, Zuo X, Chen T, Raman I (2015) A combined genome-wide DNA methylation and transcription analysis identified genes related with pathogenesis of systemic sclerosis (HUM3P.257). J Immunol 194(1 Supplement):121.117Google Scholar
  28. Lian X, Xiao R, Hu X, Kanekura T, Jiang H, Li Y, Wang Y, Yang Y, Zhao M, Lu Q (2012) DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum 64(7):2338–2345CrossRefGoogle Scholar
  29. Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus L.) Nature 190:372–373CrossRefGoogle Scholar
  30. Makol A, Reilly MJ, Rosenman KD (2011) Prevalence of connective tissue disease in silicosis (1985–2006)-a report from the state of Michigan surveillance system for silicosis. Am J Ind Med 54(4):255–262CrossRefGoogle Scholar
  31. Margadant C, Sonnenberg A (2010) Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep 11(2):97–105CrossRefGoogle Scholar
  32. Marie I, Levesque H, Ducrotte P, Denis P, Hellot MF, Benichou J, Cailleux N, Courtois H (2001) Gastric involvement in systemic sclerosis: a prospective study. Am J Gastroenterol 96(1):77–83CrossRefGoogle Scholar
  33. Marie I, Gehanno JF, Bubenheim M, Duval-Modeste AB, Joly P, Dominique S, Bravard P, Noel D, Cailleux AF, Weber J, Lagoutte P, Benichou J, Levesque H (2014) Prospective study to evaluate the association between systemic sclerosis and occupational exposure and review of the literature. Autoimmun Rev 13(2):151–156CrossRefGoogle Scholar
  34. Marie I, Menard JF, Duval-Modeste AB, Joly P, Dominique S, Bravard P, Noel D, Gehanno JF, Bubenheim M, Benichou J, Levesque H (2015) Association of occupational exposure with features of systemic sclerosis. J Am Acad Dermatol 72(3):456–464CrossRefGoogle Scholar
  35. Matouk CC, Marsden PA (2008) Epigenetic regulation of vascular endothelial gene expression. Circ Res 102(8):873–887CrossRefGoogle Scholar
  36. Maurer B, Stanczyk J, Jungel A, Akhmetshina A, Trenkmann M, Brock M, Kowal-Bielecka O, Gay RE, Michel BA, Distler JH, Gay S, Distler O (2010) MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum 62(6):1733–1743CrossRefGoogle Scholar
  37. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48(8):2246–2255CrossRefGoogle Scholar
  38. Nietert PJ, Sutherland SE, Silver RM, Pandey JP, Knapp RG, Hoel DG, Dosemeci M (1998) Is occupational organic solvent exposure a risk factor for scleroderma? Arthritis Rheum 41(6):1111–1118CrossRefGoogle Scholar
  39. Philen RM, Posada de la Paz M, Hill RH, Schurz HH, Abaitua Borda I, Gomez de la Camara A, Kilbourne EM (1997) Epidemiology of the toxic oil syndrome. Arch Toxicol Suppl 19:41–52CrossRefGoogle Scholar
  40. Pollard KM (2016) Silica, silicosis, and autoimmunity. Front Immunol 7:97CrossRefGoogle Scholar
  41. Posada de la Paz M, Abaitua Borda I, Kilbourne EM, Tabuenca Oliver JM, Diaz de Rojas F, Castro Garcia M (1989) Late cases of toxic oil syndrome: evidence that the aetiological agent persisted in oil stored for up to one year. Food Chem Toxicol 27(8):517–521CrossRefGoogle Scholar
  42. Povey A, Guppy MJ, Wood M, Knight C, Black CM, Silman AJ (2001) Cytochrome P2 polymorphisms and susceptibility to scleroderma following exposure to organic solvents. Arthritis Rheum 44(3):662–665CrossRefGoogle Scholar
  43. Qi Q, Guo Q, Tan G, Mao Y, Tang H, Zhou C, Zeng F (2009) Predictors of the scleroderma phenotype in fibroblasts from systemic sclerosis patients. J Eur Acad Dermatol Venereol 23(2):160–168CrossRefGoogle Scholar
  44. Reinl W (1957) Scleroderma caused by trichloroethylene effects. Zentralbl Arbeitsmed 7(3):58–60PubMedGoogle Scholar
  45. Rohrich RJ (1999) Safety of silicone breast implants: scientific validation/vindication at last. Plast Reconstr Surg 104(6):1786–1788CrossRefGoogle Scholar
  46. Romero LI, Zhang DN, Cooke JP, Ho HK, Avalos E, Herrera R, Herron GS (2000) Differential expression of nitric oxide by dermal microvascular endothelial cells from patients with scleroderma. Vasc Med 5(3):147–158CrossRefGoogle Scholar
  47. Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L (2010) Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum 62(9):2787–2795CrossRefGoogle Scholar
  48. Sing T, Jinnin M, Yamane K, Honda N, Makino K, Kajihara I, Makino T, Sakai K, Masuguchi S, Fukushima S, Ihn H (2012) microRNA-92a expression in the sera and dermal fibroblasts increases in patients with scleroderma. Rheumatology (Oxford) 51(9):1550–1556CrossRefGoogle Scholar
  49. Steen VD, Medsger TA (1998) Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 41(9):1613–1619CrossRefGoogle Scholar
  50. Steen V, Domsic RT, Lucas M, Fertig N, Medsger TA Jr (2012) A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum 64(9):2986–2994CrossRefGoogle Scholar
  51. Stummvoll GH, Aringer M, Grisar J, Steiner CW, Smolen JS, Knobler R, Graninger WB (2004) Increased transendothelial migration of scleroderma lymphocytes. Ann Rheum Dis 63(5):569–574CrossRefGoogle Scholar
  52. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee (1980) Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23(5):581–590CrossRefGoogle Scholar
  53. Swygert LA, Back EE, Auerbach SB, Sewell LE, Falk H (1993) Eosinophilia-myalgia syndrome: mortality data from the US national surveillance system. J Rheumatol 20(10):1711–1717PubMedGoogle Scholar
  54. Tabuenca JM (1981) Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet 2(8246):567–568CrossRefGoogle Scholar
  55. Thombs BD, Bassel M, McGuire L, Smith MT, Hudson M, Haythornthwaite JA (2008) A systematic comparison of fatigue levels in systemic sclerosis with general population, cancer and rheumatic disease samples. Rheumatology 47(10):1559–1563CrossRefGoogle Scholar
  56. Tsou PS, Wren JD, Amin MA, Schiopu E, Fox DA, Khanna D, Sawalha AH (2016) Histone deacetylase 5 is overexpressed in scleroderma endothelial cells and impairs angiogenesis via repression of proangiogenic factors. Arthritis Rheum 68(12):2975–2985CrossRefGoogle Scholar
  57. Tyndall AJ, Bannert B, Vonk M, Airo P, Cozzi F, Carreira PE, Bancel DF, Allanore Y, Muller-Ladner U, Distler O, Iannone F, Pellerito R, Pileckyte M, Miniati I, Ananieva L, Gurman AB, Damjanov N, Mueller A, Valentini G, Riemekasten G, Tikly M, Hummers L, Henriques MJS, Caramaschi P, Scheja A, Rozman B, Ton E, Kumanovics G, Coleiro B, Feierl E, Szucs G, Von Muhlen CA, Riccieri V, Novak S, Chizzolini C, Kotulska A, Denton C, Coelho PC, Kotter I, Simsek I, Lefebvre PGD, Hachulla E, Seibold JR, Rednic S, Stork J, Morovic-Vergles J, Walker UA (2010) Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 69(10):1809–1815CrossRefGoogle Scholar
  58. Urbich C, Rossig L, Kaluza D, Potente M, Boeckel JN, Knau A, Diehl F, Geng JG, Hofmann WK, Zeiher AM, Dimmeler S (2009) HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells. Blood 113(22):5669–5679CrossRefGoogle Scholar
  59. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Muller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 65(11):2737–2747CrossRefGoogle Scholar
  60. Wang Y, Kahaleh B (2007) Epigenetic regulation in scleroderma: high-throughput Dna methylation profiling of Ssc fibroblasts and microvascular endothelial cells and the central role for Nos3 and Fli1 epigenetic repression in the emergence of Ssc cellular phenotype [abstract]. Am Coll Rheumatol. Annual scientific meetingGoogle Scholar
  61. Wang YK, Kahaleh OB (2010) Down-regulated microRNA-152 induces aberrant DNA methylation in scleroderma endothelial cells by targeting DNA methyltransferase 1 [Abstract]. Arthritis Rheum 62(Suppl 10):1352Google Scholar
  62. Wang Y, Kahaleh B (2013) Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. J Cell Mol Med 17:1291–1299CrossRefGoogle Scholar
  63. Wang Y, Fan PS, Kahaleh B (2006) Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 54(7):2271–2279CrossRefGoogle Scholar
  64. Wang Y, Yang Y, Luo Y, Yin Y, Wang Q, Li Y, Kanekura T, Wang J, Liang G, Zhao M, Lu Q, Xiao R (2013) Aberrant histone modification in peripheral blood B cells from patients with systemic sclerosis. Clin Immunol 149(1):46–54CrossRefGoogle Scholar
  65. Wang Y, Shu Y, Xiao Y, Wang Q, Kanekura T, Li Y, Wang J, Zhao M, Lu Q, Xiao R (2014) Hypomethylation and overexpression of ITGAL (CD11a) in CD4(+) T cells in systemic sclerosis. Clin Epigenetics 6(1):25CrossRefGoogle Scholar
  66. Ward AM, Udnoon S, Watkins J, Walker AE, Darke CS (1976) Immunological mechanisms in the pathogenesis of vinyl chloride disease. Br Med J 1(6015):936–938CrossRefGoogle Scholar
  67. Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, Gottardi CJ, MacDougald OA, Varga J (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 63(6):1707–1717CrossRefGoogle Scholar
  68. Wei J, Ghosh AK, Chu H, Fang F, Hinchcliff ME, Wang J, Marangoni RG, Varga J (2015) The histone deacetylase sirtuin 1 is reduced in systemic sclerosis and abrogates fibrotic responses by targeting transforming growth factor beta signaling. Arthritis Rheum 67(5):1323–1334CrossRefGoogle Scholar
  69. Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK, Shin ES, Reveille JD, Mayes MD, Kim JH, Song R, Choi JY, Park JA, Lee YJ, Lee EY, Song YW, Lee EB (2009) HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum 60(12):3807–3814CrossRefGoogle Scholar
  70. Zhu H, Li Y, Qu S, Luo H, Zhou Y, Wang Y, Zhao H, You Y, Xiao X, Zuo X (2012) MicroRNA expression abnormalities in limited cutaneous scleroderma and diffuse cutaneous scleroderma. J Clin Immunol 32(3):514–522CrossRefGoogle Scholar
  71. Zhu H, Luo H, Li Y, Zhou Y, Jiang Y, Chai J, Xiao X, You Y, Zuo X (2013) MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. J Clin Immunol 33(6):1100–1109CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Rheumatology, Department of Internal MedicineUniversity of Toledo Medical CenterToledoUSA

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