Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 146 No. 2122 (2016)

Epigenetic biomarkers in rheumatology – the future?

  • Caroline Ospelt
DOI
https://doi.org/10.4414/smw.2016.14312
Cite this as:
Swiss Med Wkly. 2016;146:w14312
Published
22.05.2016

Summary

Epigenetic changes are stable modifications of DNA or histones that profoundly alter gene expression. They can be changed by environmental influences and can then be passed on to daughter cells or via the germ line to offspring. A variety of changes in epigenetic marks and in the expression of noncoding RNA has been found in cancer as well as in chronic inflammatory diseases. Interestingly, in both diseases similar mechanisms and pathways are affected albeit often to a different extent. DNA methylation is often lost in repetitive sequences, while in promoter regions hypo- as well as hypermethylation is found. Changes in microRNA levels typically affect microRNAs that are changed by an inflammatory environment, but disease specific changes have also been found in the blood and various cell types of patients with rheumatoid arthritis, systemic lupus erythematosus and other rheumatic diseases. Therefore, changes in the expression of microRNA in particular, but also demethylated gene loci, have been proposed as potential biomarkers in chronic inflammatory diseases and in cancer. Potentially, these changes could be used for early diagnosis and also to predict treatment response. Unfortunately most studies in rheumatology up to now were not designed to validate these epigenetic changes as biomarkers. Since the cancer field is much more advanced in the usage of biomarkers for disease subclassifications and subsequent therapeutic decisions, it is worthwhile to take a closer look at the biomarkers, methods and procedures used in oncology and to see which of these could also be applied to predicting disease severity and therapeutic response in rheumatic diseases.

This article will highlight common epigenetic pathways activated in cancer and various rheumatic diseases and summarise epigenetic changes that have the potential to become biomarkers in rheumatic diseases.

Summary and outlook

In summary, epigenetic biomarkers have entered the cancer field already and are also starting to be analysed in rheumatology. Even though the field is still in its infancy, studies regarding DNA methylation and microRNA measurements in particular are promising. However, to further advance this field, studies have to be conducted that are specifically designed to validate the use of epigenetic changes and microRNA as prognostic or diagnostic biomarkers.

In patients with glioblastoma, promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is already used in clinics to predict the response to alkylating drugs, which shows that the use of DNA methylation as epigenetic biomarker is feasible. Methylation-specific PCR, as well as pyrosequencing, can be applied to measure the methylation status of a specific locus, with the first being cheap and fast and the latter being more reliable, but also more expensive. In rheumatic diseases the status of DNA methylation could be assessed in biopsies from synovial tissues of patients, in peripheral blood cells or even in cell-free DNA isolated from the blood, which is currently being explored in cancer patients [59].

In view of the costs that are spent on drugs in rheumatology and the time some patients have to wait for their diagnosis and efficient treatment, it is absolutely justified to intensify efforts to find the right diagnosis and the right treatment. This may mean that more biopsies have to be taken and more than one biomarker has to be measured – measures that are readily accepted for cancer diagnosis.

Efforts like the Encyclopedia Of DNA Elements (ENCODE) project, which aims to identify all functional elements of the genome including histone modifications and DNA methylation, have already brought valuable insights into transcript expression and are requisite for the understanding of the alterations in the epigenome that are measured in rheumatic diseases. But to understand epigenetic changes in rheumatic diseases is probably not enough. As in the cancer genome atlas (TCGA), the rheumatology research community should aim to map molecular pathways that drive rheumatic diseases and connect changes in the genome, the epigenome, transcription, protein expression and clinical outcomes. Potential biomarkers or combination of biomarkers must then be selected and tested in studies with an appropriate study design. This strategy would not only bring us closer to finding diagnostic, predictive and prognostic biomarkers, but would also help to find new therapeutic targets.

References

  1. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7):781–3.
  2. Bird A. Perceptions of epigenetics. Nature. 2007;447(7143):396–8.
  3. Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358(11):1148–59.
  4. Koch MW, Metz LM, Kovalchuk O. Epigenetic changes in patients with multiple sclerosis. Nat Rev Neurol. 2013;9(1):35–43.
  5. Klein K, Gay S. Epigenetics in rheumatoid arthritis. Curr Opin Rheumatol. 2015;27(1):76–82.
  6. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009;1(2):239–59.
  7. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2009;60(12):3613–22.
  8. Karouzakis E, Rengel Y, Jungel A, Kolling C, Gay RE, Michel BA, et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun. 2011;12(8):643–52.
  9. Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, et al. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum. 2006;54(3):779-87.
  10. McCabe MT, Brandes JC, Vertino PM. Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res. 2009;15(12):3927–37.
  11. Whitaker JW, Shoemaker R, Boyle DL, Hillman J, Anderson D, Wang W, et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med. 2013;5(4):40.
  12. Nakano K, Whitaker JW, Boyle DL, Wang W, Firestein GS. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72(1):110–7.
  13. Absher DM, Li X, Waite LL, Gibson A, Roberts K, Edberg J, et al. Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS genetics. 2013;9(8):e1003678.
  14. Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A, et al. Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis Rheumatol. 2014;66(3):731–9.
  15. Furumitsu Y, Yukioka K, Kojima A, Yukioka M, Shichikawa K, Ochi T, et al. Levels of urinary polyamines in patients with rheumatoid arthritis. J Rheumatol. 1993;20(10):1661–5.
  16. Karouzakis E, Gay RE, Gay S, Neidhart M. Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2012;64(6):1809–17.
  17. Gerner EW, Meyskens FL, Jr. Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer. 2004;4(10):781–92.
  18. Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 2014;156(1-2):45–68.
  19. Cimmino L, Abdel-Wahab O, Levine RL, Aifantis I. TET family proteins and their role in stem cell differentiation and transformation. Cell Stem Cell. 2011;9(3):193–204.
  20. de Andres MC, Perez-Pampin E, Calaza M, Santaclara FJ, Ortea I, Gomez-Reino JJ, et al. Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res Ther. 2015;17:233.
  21. Quintero-Ronderos P, Montoya-Ortiz G. Epigenetics and autoimmune diseases. Autoimmune Dis. 2012;2012:593720.
  22. Sandoval J, Esteller M. Cancer epigenomics: beyond genomics. Curr Opin Genet Dev. 2012;22(1):50–5.
  23. Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, et al. A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell. 2006;126(6):1203–17.
  24. Vicente R, Noel D, Pers YM, Apparailly F, Jorgensen C. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nat Rev Rheumatol. 2015.
  25. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.
  26. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27(34):5743–50.
  27. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142–7.
  28. Chechlinska M, Kowalewska M, Nowak R. Systemic inflammation as a confounding factor in cancer biomarker discovery and validation. Nat Rev Cancer. 2010;10(1):2–3.
  29. Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 2008;58(9):2686–93.
  30. Mikeska T, Craig JM. DNA methylation biomarkers: cancer and beyond. Genes (Basel). 2014;5(3):821–64.
  31. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11(6):426–37.
  32. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson M. Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 1990;33(11):1665–73.
  33. Corvetta A, Della Bitta R, Luchetti MM, Pomponio G. 5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases. J Chromatogr. 1991;566(2):481–91.
  34. Karouzakis E, Trenkmann M, Gay RE, Michel BA, Gay S, Neidhart M. Epigenome Analysis Reveals TBX5 as a Novel Transcription Factor Involved in the Activation of Rheumatoid Arthritis Synovial Fibroblasts. J Immunol. 2014;193(10):4945–51.
  35. Ai R, Whitaker JW, Boyle DL, Tak PP, Gerlag DM, Wang W, et al. DNA Methylome Signature in Synoviocytes From Patients With Early Rheumatoid Arthritis Compared to Synoviocytes From Patients With Longstanding Rheumatoid Arthritis. Arthritis Rheumatol. 2015;67(7):1978–80.
  36. de la Rica L, Urquiza JM, Gomez-Cabrero D, Islam AB, Lopez-Bigas N, Tegner J, et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun. 2013;41:6–16.
  37. Altorok N, Tsou PS, Coit P, Khanna D, Sawalha AH. 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. 2015;74(8):1612–20.
  38. Dees C, Schlottmann I, Funke R, Distler A, Palumbo-Zerr K, Zerr P, et al. The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis. Ann Rheum Dis. 2014;73(6):1232–9.
  39. Lian X, Xiao R, Hu X, Kanekura T, Jiang H, Li Y, et al. DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012;64(7):2338–45.
  40. Quddus J, Johnson KJ, Gavalchin J, Amento EP, Chrisp CE, Yung RL, et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice. J Clin Invest. 1993;92(1):38–53.
  41. Karouzakis E, Filer A, Eyre S, Raza K, Kolling C, Gay RE, et al. Genetic and Epigenetic Mapping of Very Early RA Synovial Fibroblasts [abstract]. Arthritis Rheumatol. 2015;67(supplement 10).
  42. Zhao M, Zhou Y, Zhu B, Wan M, Jiang T, Tan Q, et al. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis. 2016.
  43. Plant D, Webster A, Nair N, Oliver J, Smith S, Eyre S, et al. Differential methylation as a biomarker of response to etanercept in patients with rheumatoid arthritis. Arthritis Rheumatol. 2016. [epub ahead of print].
  44. Cribbs AP, Kennedy A, Penn H, Amjadi P, Green P, Read JE, et al. Methotrexate Restores Regulatory T Cell Function Through Demethylation of the FoxP3 Upstream Enhancer in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2015;67(5):1182–92.
  45. Gay S, Wilson AG. The emerging role of epigenetics in rheumatic diseases. Rheumatology (Oxford). 2014;53(3):406–14.
  46. Liang Y, Ridzon D, Wong L, Chen C. Characterization of microRNA expression profiles in normal human tissues. BMC Genomics. 2007;8:166.
  47. Stanczyk J, Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, et al. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008;58(4):1001–9.
  48. Kyburz D, Karouzakis E, Ospelt C. Epigenetic changes: the missing link. Best Pract Res Clin Rheumatol. 2014;28(4):577–87.
  49. Olivieri F, Rippo MR, Procopio AD, Fazioli F. Circulating inflamma-miRs in aging and age-related diseases. Front Genet. 2013;4:121.
  50. Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y, et al. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis RheumArthritis. 2009;60(4):1065–75.
  51. Duroux-Richard I, Jorgensen C, Apparailly F. miRNAs and rheumatoid arthritis - promising novel biomarkers. Swiss Med Wkly. 2011;141:w13175.
  52. Carlsen AL, Schetter AJ, Nielsen CT, Lood C, Knudsen S, Voss A, et al. Circulating microRNA expression profiles associated with systemic lupus erythematosus. Arthritis RheumArthritis. 2013;65(5):1324–34.
  53. Steen SO, Iversen LV, Carlsen AL, Burton M, Nielsen CT, Jacobsen S, et al. The circulating cell-free microRNA profile in systemic sclerosis is distinct from both healthy controls and systemic lupus erythematosus. J Rheumatol. 2015;42(2):214–21.
  54. Murata K, Furu M, Yoshitomi H, Ishikawa M, Shibuya H, Hashimoto M, et al. Comprehensive microRNA analysis identifies miR-24 and miR-125a-5p as plasma biomarkers for rheumatoid arthritis. PLoS One. 2013;8(7):e69118.
  55. Kamiya Y, Kawada J, Kawano Y, Torii Y, Kawabe S, Iwata N, et al. Serum microRNAs as Potential Biomarkers of Juvenile Idiopathic Arthritis. Clin Rheumatol. 2015;34(10):1705–12.
  56. Castro-Villegas C, Perez-Sanchez C, Escudero A, Filipescu I, Verdu M, Ruiz-Limon P, et al. Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFalpha. Arthritis Res Ther. 2015;17:49.
  57. Krintel SB, Dehlendorff C, Hetland ML, Horslev-Petersen K, Andersen KK, Junker P, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2015.
  58. Duroux-Richard I, Pers YM, Fabre S, Ammari M, Baeten D, Cartron G, et al. Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis. Mediators Inflamm. 2014;2014:342524.
  59. Warton K, Samimi G. Methylation of cell-free circulating DNA in the diagnosis of cancer. Front Mol Biosci. 2015;2:13.