Skip to main content

Advertisement

SpringerLink
Log in

Epigenetics of Multiple Sclerosis: An Updated Review

  • Review Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein–Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels and treatment methods with specific mechanism of action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Agarwal, S., & Rao, A. (1998). Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity, 9, 765–775.

    CAS  PubMed  Google Scholar 

  • Alevizos, I., & Illei, G. G. (2010). MicroRNAs in Sjogren’s syndrome as a prototypic autoimmune disease. Autoimmunity Reviews, 9, 618–621.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ascherio, A., & Munger, K. L. (2007). Environmental risk factors for multiple sclerosis. Part I: The role of infection. Annals of Neurology, 61, 288–299.

    PubMed  Google Scholar 

  • Balada, E., Ordi-Ros, J., & Vilardell-Tarres, M. (2007). DNA methylation and systemic lupus erythematosus. Annals of the New York Academy of Sciences, 1108, 27–136.

    Google Scholar 

  • Balada, E., Ordi-Ros, J., & Vilardell-Tarrés, M. (2009). Molecular mechanisms mediated by human endogenous retroviruses (HERVs) in autoimmunity. Reviews in Medical Virology, 19, 273–286.

    CAS  PubMed  Google Scholar 

  • Ballestar, E. (2010). Epigenetics lessons from twins: Prospects for autoimmune disease. Clinical Reviews in Allergy and Immunology, 39, 30–41.

    CAS  PubMed  Google Scholar 

  • Baranzini, S. E., Mudge, J., van Velkinburgh, J. C., et al. (2010). Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature, 464, 1351–1356.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Baranzini, S. E., & Nickles, D. (2012). Genetics of multiple sclerosis: Swimming in an ocean of data. Current Opinion in Neurology, 25, 239–245.

    PubMed  Google Scholar 

  • Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.

    CAS  PubMed  Google Scholar 

  • Bestor, T. H. (2000). The DNA methyltransferases of mammals. Human Molecular Genetics, 9, 2395–2402.

    CAS  PubMed  Google Scholar 

  • Bulosan, M., Pauley, K. M., Yo, K., Chan, E. K., Katz, J., Peck, A. B., et al. (2009). Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjogren’s syndrome before disease onset. Immunology and Cell Biology, 87, 81–90.

    CAS  PubMed  Google Scholar 

  • Calabrese, R., Zampieri, M., Mechelli, R., Annibali, V., Guastafierro, T., Ciccarone, F., et al. (2012). Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood. Multiple Sclerosis Journal, 18, 299–304.

    CAS  PubMed  Google Scholar 

  • Camelo, S., Iglesias, A. H., Hwang, D., Due, B., Ryu, H., Smith, K., et al. (2005). Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 164, 10–21.

    CAS  PubMed  Google Scholar 

  • Carrillo-Vico, A., Leech, M. D., & Anderton, S. M. (2010). Contribution of myelin autoantigen citrullination to T cell autoaggression in the central nervous system. The Journal of Immunology, 184, 2839–2846.

    CAS  PubMed  Google Scholar 

  • Chang, T. C., & Mendell, J. T. (2007). microRNAs in vertebrate physiology and human disease. Annual Review of Genomics and Human Genetics, 8, 215–239.

    CAS  PubMed  Google Scholar 

  • Chiang, E. P., Wang, Y. C., Chen, W. W., & Tang, F. Y. (2009). Effects of insulin and glucose on cellularmetabolic fluxes in homocysteine transsulfuration, remethylation, S-adenosylmethionine synthesis, and global deoxyribonucleic acid methylation. Journal of Clinical Endocrinology and Metabolism, 94, 1017–1025.

    CAS  PubMed  Google Scholar 

  • Christophi, G. P., Hudson, C. A., Gruber, R. C., Christophi, C. P., Mihai, C., Mejico, L. J., et al. (2008). SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients. Laboratory Investigation, 88, 243–255.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Christophi, G. P., Panos, M., Hudson, C. A., Tsikkou, C., Mihai, C., Mejico, L. J., et al. (2009). Interferon-β treatment in multiple sclerosis attenuates inflammatory gene expression through inducible activity of the phosphatase SHP-1. Clinical Immunology, 133, 27–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coquet, J. M., Middendorp, S., van der Horst, G., Kind, J., Veraar, E. A., Xiao, Y., et al. (2013). The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity, 38, 53–65.

    CAS  PubMed  Google Scholar 

  • Cox, M. B., Cairns, M. J., Gandhi, K. S., Carroll, A. P., Moscovis, S., Stewart, G. J., et al. (2010). MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One, 5, e12132.

    PubMed Central  PubMed  Google Scholar 

  • D’Souza, C. A., Wood, D. D., She, Y. M., & Moscarello, M. A. (2005). Autocatalytic cleavage of myelin basic protein: An alternative to molecular mimicry. Biochemistry, 44, 12905–12913.

    PubMed  Google Scholar 

  • Deng, C., Lu, Q., Zhang, Z., Rao, T., Attwood, J., Yung, R., et al. (2003). Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis and Rheumatism, 48, 746–756.

    CAS  PubMed  Google Scholar 

  • Du, C., Liu, C., Kang, J., Zhao, G., Ye, Z., Huang, S., et al. (2009). MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nature Immunology, 10, 1252–1259.

    CAS  PubMed  Google Scholar 

  • Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: Definition, mechanisms and clinical perspective. Seminars in Reproductive Medicine, 27, 351–357.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ebers, G. C., et al. (2004). Parent-of-origin effect in multiple sclerosis: Observations in half-siblings. Lancet, 363, 1773–1774.

    CAS  PubMed  Google Scholar 

  • Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457–463.

    CAS  PubMed  Google Scholar 

  • Escobar, T., Yu, C. R., Muljo, S. A., & Egwuagu, C. E. (2013). STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis. Investigative Ophthalmology & Visual Science, 54, 4017–4025.

    CAS  Google Scholar 

  • Ezhkova, E., Pasolli, H. A., Parker, J. S., Stokes, N., Su, I. H., Hannon, G., et al. (2009). Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell, 136, 1122–1135.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fali, T., Le Dantec, C., Thabet, Y., Jousse, S., Hanrotel, C., Youinou, P., et al. (2013). DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus. Autoimmunity,. doi:10.3109/08916934.2013.826207.

    PubMed Central  PubMed  Google Scholar 

  • Faraco, G., et al. (2011). The therapeutic potential of HDAC inhibitors in the treatment of multiple sclerosis. Molecular Medicine, 17, 442–447.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fatemi, M., Pao, M. M., Jeong, S., Gal-Yam, E. N., Egger, G., Weisenberger, D. J., et al. (2005). Footprinting of mammalian promoters: Use of a CpG DNA methyltransferase revealing nucleosome positions at a single molecule level. Nucleic Acids Research, 33, e176.

    PubMed Central  PubMed  Google Scholar 

  • Fraga, M. F., Ballestar, E., Paz, M. F., et al. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences of the United States of America, 102, 10604–10609.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gao, B., Kong, Q., Kemp, K., Zhao, Y. S., & Fang, D. (2012). Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. Proceedings of the National Academy of Sciences of the United States of America, 109, 899–904.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Goodell, M. A., & Godley, L. A. (2013). Perspectives and future directions for epigenetics in hematology. Blood, 121, 5131–5137.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gourraud, P. A., Harbo, H. F., Hauser, S. L., & Baranzini, S. E. (2012). The genetics of multiple sclerosis: An up-to-date review. Immunological Reviews, 248, 87–103.

    PubMed  Google Scholar 

  • Grabiec, A. M., Tak, P. P., & Reedquist, K. A. (2008). Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: Should we keep our HATs on? Arthritis Research and Therapy, 10, 226.

    PubMed Central  PubMed  Google Scholar 

  • Graves, M., Benton, M., Lea, R., Boyle, M., Tajouri, L., Macartney-Coxson, D., et al. (2013). Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. Mult: Scler. doi:10.1177/1352458513516529.

    Google Scholar 

  • Gray, S. G., & Dangond, F. (2006). Rationale for the use of histone deacetylase inhibitors as a dual therapeutic modality in multiple sclerosis. Epigenetics, 1, 67–75.

    PubMed  Google Scholar 

  • Grogan, J. L., Mohrs, M., Harmon, B., et al. (2001). Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity, 14, 205–215.

    CAS  PubMed  Google Scholar 

  • Guan, H., Nagarkatti, P. S., & Nagarkatti, M. (2011). CD44 Reciprocally regulates the differentiation of encephalitogenic Th1/Th17 and Th2/regulatory T cells through epigenetic modulation involving DNA methylation of cytokine gene promoters, thereby controlling the development of experimental autoimmune encephalomyelitis. The Journal of Immunology, 186, 6955–6964.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Haasch, D., Chen, Y. W., Reilly, R. M., Chiou, X. G., Koterski, S., Smith, M. L., et al. (2002). T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cellular Immunology, 217, 78–86.

    CAS  PubMed  Google Scholar 

  • Hauser, S. L., & Oksenberg, J. R. (2006). The neurobiology of multiple sclerosis: Genes, inflammation, and neurodegeneration. Neuron, 52, 61–76.

    CAS  PubMed  Google Scholar 

  • Hecker, M., Thamilarasan, M., Koczan, D., Schröder, I., Flechtner, K., Freiesleben, S., et al. (2013). MicroRNA expression changes during interferon-beta treatment in the peripheral blood of multiple sclerosis patients. International Journal of Molecular Sciences, 14, 16087–16110.

    PubMed Central  PubMed  Google Scholar 

  • Hernán, M. A., Olek, M. J., & Ascherio, A. (2001). Cigarette smoking and incidence of multiple sclerosis. American Journal of Epidemiology, 154, 69–74.

    PubMed  Google Scholar 

  • Hu, N., Qiu, X., Luo, Y., et al. (2008). Abnormal histone modification patterns in lupus CD4+ T cells. Journal of Rheumatology, 35, 804–810.

    CAS  PubMed  Google Scholar 

  • Huber, L. C., Brock, M., Hemmatazad, H., Giger, O. T., Moritz, F., Trenkmann, M., et al. (2007). Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis and Rheumatism, 56, 1087–1093.

    CAS  PubMed  Google Scholar 

  • Huynh, J. L., & Casaccia, P. (2013). Epigenetic mechanisms in multiple sclerosis: Implications for pathogenesis and treatment. Lancet Neurology, 12, 195–206.

    PubMed Central  CAS  Google Scholar 

  • Inkster, B., Strijbis, E. M., Vounou, M., Kappos, L., Radue, E. W., Matthews, P. M., et al. (2013). Histone deacetylase gene variants predict brain volume changes in multiple sclerosis. Neurobiology of Aging, 34, 238–247.

    CAS  PubMed  Google Scholar 

  • Jacob, C., Christen, C. N., Pereira, J. A., Somandin, C., Baggiolini, A., Lötscher, P., et al. (2011). HDAC1 and HDAC2 control the transcriptional program of myelination and the survival of Schwann cells. Nature Neuroscience, 14, 429–436.

    CAS  PubMed  Google Scholar 

  • Januchowski, R., Wudarski, M., Chwalińska-Sadowska, H., & Jagodzinski, P. P. (2008). Prevalence of ZAP-70, LAT, SLP-76, and DNMT1 expression in CD4+ T cells of patients with SLE. Clinical Rheumatology, 27, 21–27.

    PubMed  Google Scholar 

  • Junker, A., Krumbholz, M., Eisele, S., et al. (2009). MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain, 132, 3342–3352.

    PubMed  Google Scholar 

  • Kaplan, M. J., Lu, Q., Wu, A., Attwood, J., & Richardson, B. (2004). Demethylation of promoter regulatory elements contributes to perforin overexpression in CD41 lupus T cells. The Journal of Immunology, 172, 3652–3661.

    CAS  PubMed  Google Scholar 

  • Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S., & Neidhart, M. (2009). DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 60, 3613–3622.

    CAS  PubMed  Google Scholar 

  • Keller, A., Leidinger, P., Lange, J., Borries, A., Schroers, H., Scheffler, M., et al. (2009). Multiple sclerosis: microRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS One, 4, e7440.

    PubMed Central  PubMed  Google Scholar 

  • Koch, M., Kingwell, E., Rieckmann, P., & Tremlett, H. (2009). The natural history of primary progressive multiple sclerosis. Neurology, 73, 1996–2002.

    PubMed  Google Scholar 

  • Koch, M. W., Metz, L. M., & Kovalchuk, O. (2013a). Epigenetics and miRNAs in the diagnosis and treatment of multiple sclerosis. Trends in Molecular Medicine, 19, 23–30.

    CAS  PubMed  Google Scholar 

  • Koch, M. W., Metz, L. M., & Kovalchuk, O. (2013b). Epigenetic changes in patients with multiple sclerosis. Nature Reviews Neurology, 9, 35–43.

    CAS  PubMed  Google Scholar 

  • Korganow, A. S., Knapp, A. M., Nehme-Schuster, H., Soulas-Sprauel, P., Poindron, V., Pasquali, J. L., et al. (2010). Peripheral B cell abnormalities in patients with systemic lupus erythematosus in quiescent phase: Decreased memory B cells and membrane CD19 expression. Journal of Autoimmunity, 34, 426–434.

    CAS  PubMed  Google Scholar 

  • Kouzarides, T. (2007). Chromatin modifications and their function. Cell, 128, 693–705.

    CAS  PubMed  Google Scholar 

  • Kremer, D., Schichel, T., Förster, M., Tzekova, N., Bernard, C., van der Valk, P., et al. (2013). Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann: Neurol. doi:10.1002/ana.23970.

    Google Scholar 

  • Kumagai, C., Kalman, B., Middleton, F. A., Vyshkina, T., & Massa, P. T. (2012). Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. Journal of Neuroimmunology, 246, 51–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lal, G., Zhang, N., van der Touw, W., et al. (2009). Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. The Journal of Immunology, 182, 259–273.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lauer, K. (2010). Environmental risk factors in multiple sclerosis. Expert Review of Neurotherapeutics, 10, 421–440.

    PubMed  Google Scholar 

  • Lee, B. H., Yegnasubramanian, S., Lin, X., & Nelson, W. G. (2005). Procainamide is a specific inhibitor of DNA methyltransferase 1. Journal of Biological Chemistry, 280, 40749–40756.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lei, W., Luo, Y., Lei, W., et al. (2009). Abnormal DNA methylation in CD4+ T cells from patients with SLE, systemic sclerosis, and dermatomyositis. Scandinavian Journal of Rheumatology, 38, 369–374.

    CAS  PubMed  Google Scholar 

  • Li, H., & Richardson, W. D. (2009). Genetics meets epigenetics: HDACs and Wnt signaling in myelin development and regeneration. Nature Neuroscience, 12, 815–817.

    CAS  PubMed  Google Scholar 

  • Liggett, T., Melnikov, A., Tilwalli, S., Yi, Q., Chen, H., Replogle, C., et al. (2010). Methylation patterns of cell-free plasma DNA in relapsing-remitting multiple sclerosis. Journal of the Neurological Sciences, 290, 16–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu, Y., Chen, Y., & Richardson, B. (2009). Decreased DNA methyltransferase levels contribute to abnormal gene expression in “senescent” CD4(+) CD28(−) T cells. Clin. Immunol., 132, 257–265.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu, B., Tahk, S., Yee, K. M., Fan, G., & Shuai, K. (2010). The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science, 330, 521–525.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lu, Q., Wu, A., & Richardson, B. C. (2005). Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. The Journal of Immunology, 174, 6212–6219.

    CAS  PubMed  Google Scholar 

  • Lu, Q., Wu, A., Tesmer, L., Ray, D., Yousif, N., & Richardson, B. (2007). Demethylation of CD40LG on the inactive X in T cells from women with lupus. The Journal of Immunology, 179, 6352–6358.

    CAS  PubMed  Google Scholar 

  • Ma, J., Wang, R., Fang, X., Ding, Y., & Sun, Z. (2011). Critical role of TCF-1 in repression of the IL-17 gene. PLoS One, 6, e24768.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Makar, K. W., & Wilson, C. B. (2004). DNA methylation is a nonredundant repressor of the Th2 effector program. The Journal of Immunology, 173, 4402–4406.

    CAS  PubMed  Google Scholar 

  • Marin-Husstege, M., Muggironi, M., Liu, A., & Casaccia-Bonnefil, P. (2002). Histone deacetylase activity is necessary for oligodendrocyte lineage progression. Journal of Neuroscience, 22, 10333–10345.

    CAS  PubMed  Google Scholar 

  • Mastronardi, F. G., Noor, A., Wood, D. D., Paton, T., & Moscarello, M. A. (2007). Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. Journal of Neuroscience Research, 85, 2006–2016.

    CAS  PubMed  Google Scholar 

  • Mastronardi, F. G., Wood, D. D., Mei, J., Raijmakers, R., Tseveleki, V., Dosch, H. M., et al. (2006). Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: A role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. Journal of Neuroscience, 26, 11387–11396.

    CAS  PubMed  Google Scholar 

  • Mazari, L., Ouarzane, M., & Zouali, M. (2007). Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus. Proceedings of the National Academy of Sciences of the United States of America, 104, 6317–6322.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mikovits, J. A., Young, H. A., Vertino, P., et al. (1998). Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-gamma) promoter and subsequent downregulation of IFN-γ production. Molecular and Cellular Biology, 18, 5166–5177.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mishra, N., Reilly, C. M., Brown, D. R., Ruiz, P., & Gilkeson, G. S. (2003). Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. Journal of Clinical Investigation, 111, 539–552.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Moscarello, M. A., Brady, G. W., Fein, D. B., Wood, D. D., & Cruz, T. F. (1986). The role of charge microheterogeneity of basic protein in the formation and maintenance of the multilayered structure of myelin: A possible role in multiple sclerosis. Journal of Neuroscience Research, 15, 87–99.

    CAS  PubMed  Google Scholar 

  • Moscarello, M. A., Wood, D. D., Ackerley, C., & Boulias, C. (1994). Myelin in multiple sclerosis is developmentally immature. Journal of Clinical Investigation, 94, 146–154.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mullen, A. C., Hutchins, A. S., Villarino, A. V., et al. (2001). Cell cycle controlling the silencing and functioning of mammalian activators. Current Biology, 11, 1695–1699.

    CAS  PubMed  Google Scholar 

  • Muñoz-Culla, M., Irizar, H., & Otaegui, D. (2013). The genetics of multiple sclerosis: Review of current and emerging candidates. Application of Clinical Genetics, 6, 63–73.

    PubMed Central  PubMed  Google Scholar 

  • Murugaiyan, G., Beynon, V., Mittal, A., Joller, N., & Weiner, H. L. (2011). Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. The Journal of Immunology, 187, 2213–2221.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Musse, A. A., Boggs, J. M., & Harauz, G. (2006). Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope. Proceedings of the National Academy of Sciences of the United States of America, 103, 4422–4427.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Musse, A. A., Li, Z., Ackerley, C. A., Bienzle, D., Lei, H., Poma, R., et al. (2008). Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Disease Models and Mechanisms, 1, 229–240.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nakkuntod, J., Avihingsanon, Y., Mutirangura, A., & Hirankarn, N. (2011). Hypomethylation of LINE-1 but not Alu in lymphocyte subsets of systemic lupus erythematosus patients. Clinica Chimica Acta, 412, 1457–1461.

    CAS  Google Scholar 

  • Neidhart, M., Rethage, J., Kuchen, S., Kunzler, P., Crowl, R. M., Billingham, M. E., et al. (2000). Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: Association with genomic DNA hypomethylation and influence on gene expression. Arthritis and Rheumatism, 43, 2634–2647.

    CAS  PubMed  Google Scholar 

  • Nieves, J., Cosman, F., Herbert, J., Shen, V., & Lindsay, R. (1994). High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology, 44, 1687–1692.

    CAS  PubMed  Google Scholar 

  • Noorbakhsh, F., Ellestad, K. K., Maingat, F., Warren, K. G., Han, M. H., Steinman, L., et al. (2011). Impaired neurosteroid synthesis in multiple sclerosis. Brain, 134, 2703–2721.

    PubMed Central  PubMed  Google Scholar 

  • O’Connell, R. M., Kahn, D., Gibson, W. S., Round, J. L., Scholz, R. L., Chaudhuri, A. A., et al. (2010). MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity, 33, 607–619.

    PubMed Central  PubMed  Google Scholar 

  • Oelke, K., Lu, Q., Richardson, D., Wu, A., Deng, C., Hanash, S., et al. (2004). Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors. Arthritis and Rheumatism, 50, 1850–1860.

    CAS  PubMed  Google Scholar 

  • Oksenberg, J. R., & Baranzini, S. E. (2010). Multiple sclerosis genetics—Is the glass half full, or half empty? Nature Reviews Neurology, 6, 429–437.

    PubMed  Google Scholar 

  • Otaegui, D., Baranzini, S. E., Armañanzas, R., Calvo, B., Muñoz-Culla, M., Khankhanian, P., et al. (2009). Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One, 4, e6309.

    PubMed Central  PubMed  Google Scholar 

  • Pandis, I., Ospelt, C., Karagianni, N., Denis, M. C., Reczko, M., Camps, C., et al. (2012). Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model. Annals of the Rheumatic Diseases, 71, 1716–1723.

    CAS  PubMed  Google Scholar 

  • Pedre, X., Mastronardi, F., Bruck, W., Lopez-Rodas, G., Kuhlmann, T., & Casaccia, P. (2011). Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. Journal of Neuroscience, 31, 3435–3445.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Perron, H., & Lang, A. (2010). The human endogenous retrovirus link between genes and environment in multiple sclerosis and in multifactorial diseases associating neuroinflammation. Clinical Reviews in Allergy and Immunology, 39, 51–61.

    CAS  PubMed  Google Scholar 

  • Pritzker, L. B., Joshi, S., Gowan, J. J., Harauz, G., & Moscarello, M. A. (2000). Deimination of myelin basic protein. 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D. Biochemistry, 39, 5374–5381.

    CAS  PubMed  Google Scholar 

  • Quddus, J., Johnson, K. J., Gavalchin, J., Amento, E. P., Chrisp, C. E., Yung, R. L., et al. (1993). Treating activated CD4 þ 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. Journal of Clinical Investigation, 92, 38–53.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ramagopalan, S. V., Dobson, R., Meier, U. C., & Giovannoni, G. (2010). Multiple sclerosis: Risk factors, prodromes, and potential causal pathways. Lancet Neurology, 9, 727–739.

    Google Scholar 

  • Ramagopalan, S. V., et al. (2008). Parental transmission of HLADRB1*15 in multiple sclerosis. Human Genetics, 122, 661–663.

    CAS  PubMed  Google Scholar 

  • Razin, A. (1998). CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO Journal, 17, 4905–4908.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Reik, W., Dean, W., & Walter, J. (2001). Epigenetic reprogramming in mammalian development. Science, 293, 1089–1093.

    CAS  PubMed  Google Scholar 

  • Reilly, C. M., Mishra, N., Miller, J. M., Joshi, D., Ruiz, P., Richon, V. M., et al. (2004). Modulation of renal disease in MRL/lpr mice by suberoylanilide hydroxamic acid. The Journal of Immunology, 173, 4171–4178.

    CAS  PubMed  Google Scholar 

  • Richardson, B. (1986). Effect of an inhibitor of DNA methylation on T cells. II. 5-Azacytidine induces self-reactivity in antigen-specific T4+ cells. Human Immunology, 17, 456–470.

    CAS  PubMed  Google Scholar 

  • Richardson, B., Scheinbart, L., Strahler, J., Gross, L., Hanash, S., & Johnson, M. (1990). Evidence for impaired T cell DNA methylation in SLE and rheumatoid arthritis. Arthritis and Rheumatism, 33, 1665–1673.

    CAS  PubMed  Google Scholar 

  • Saemann, M. D., Bohmig, G. A., Osterreicher, C. H., Burtscher, H., Parolini, O., Diakos, C., et al. (2000). Anti-inflammatory effects of sodium butyrate on human monocytes: Potent inhibition of IL-12 and up-regulation of IL-10 production. The FASEB Journal, 14, 2380–2382.

    CAS  Google Scholar 

  • Scott, R. J., Booth, D. R., & Lechner-Scott, J. (2010). ANZgene multiple sclerosis genetics consortium. MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One, 5, e12132.

    PubMed Central  PubMed  Google Scholar 

  • Shen, S., Sandoval, J., Swiss, V. A., et al. (2008). Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neuroscience, 11, 1024–1034.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shigaki, H., Baba, Y., Watanabe, M., Iwagami, S., Miyake, K., Ishimoto, T., et al. (2012). LINE-1 hypomethylation in noncancerous esophageal mucosae is associated with smoking history. Annals of Surgical Oncology, 19, 4238–4243.

    PubMed  Google Scholar 

  • Sievers, C., Meira, M., Hoffmann, F., Fontoura, P., Kappos, L., & Lindberg, R. L. (2012). Altered microRNA expression in B lymphocytes in multiple sclerosis: Towards a better understanding of treatment effects. Clinical Immunology, 144, 70–79.

    CAS  PubMed  Google Scholar 

  • Singer, N. G., Richardson, B. C., Powers, D., et al. (1996). Role of the CD6 glycoprotein in antigen-specific and autoreactive responses of cloned human T lymphocytes. Immunology, 88, 537–543.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Singleton, A. B., Hardy, J., Traynor, B. J., & Houlden, H. (2010). Towards a complete resolution of the genetic architecture of disease. Trends in Genetics, 26, S438–S442.

    Google Scholar 

  • Sobel, R. A. (2000). Genetic and epigenetic influence on EAE phenotypes induced with different encephalitogenic peptides. Journal of Neuroimmunology, 108, 45–52.

    CAS  PubMed  Google Scholar 

  • Swank, R. L., & Dugan, B. B. (1990). Effect of low saturated fat diet in early and late cases of multiple sclerosis. Lancet, 336, 37–39.

    CAS  PubMed  Google Scholar 

  • Teng, G., Hakimpour, P., Landgraf, P., Rice, A., Tuschl, T., Casellas, R., et al. (2008). MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity, 28, 621–629.

    PubMed Central  CAS  PubMed  Google Scholar 

  • The International Multiple Sclerosis Genetics Consortium. (2007). Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine, 357, 851–862.

    Google Scholar 

  • Tranquill, L. R., Cao, L., Ling, N. C., Kalbacher, H., Martin, R. M., & Whitaker, J. N. (2000). Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients. Multiple Sclerosis, 6, 220–225.

    CAS  PubMed  Google Scholar 

  • Urdinguio, R. G., Sanchez-Mut, J. V., & Esteller, M. (2009). Epigenetic mechanisms in neurological diseases: Genes, syndromes, and therapies. Lancet Neurology, 8, 1056–1072.

    CAS  Google Scholar 

  • Vossenaar, E. R., Zendman, A. J., van Venrooij, W. J., & Pruijn, G. J. (2003). PAD, a growing family of citrullinating enzymes: Genes, features and involvement in disease. BioEssays, 25, 1106–1118.

    CAS  PubMed  Google Scholar 

  • Waschbisch, A., Atiya, M., Linker, R. A., Potapov, S., Schwab, S., & Derfuss, T. (2011). Glatiramer acetate treatment normalizes deregulated microRNA expression in relapsing remitting multiple sclerosis. PLoS One, 6, e24604.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson, C. B., Makar, K. W., Shnyreva, B., et al. (2005). DNA methylation and the expanding epigenetics of T cell lineage commitment. Seminars in Immunology, 17, 105–119.

    CAS  PubMed  Google Scholar 

  • Yang, H., Lee, S. M., Gao, B., Zhang, J., & Fang, D. (2013). The histone deacetylase Sirtuin 1 deacetylates IRF1 and programs dendritic cells to control Th17 differentiation during autoimmune inflammation. Journal of Biological Chemistry,. doi:10.1074/jbc.M113.527531.

    Google Scholar 

  • Yoshida, M., Kijima, M., Akita, M., & Beppu, T. (1990). Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. Journal of Biological Chemistry, 265, 17174–17179.

    CAS  PubMed  Google Scholar 

  • Young, H. A., Dray, J. F., & Farrar, W. L. (1986). Expression of transfected human interferon-gamma DNA: Evidence for cell-specific regulation. The Journal of Immunology, 136, 4700–4703.

    CAS  PubMed  Google Scholar 

  • Young, H. A., Ghosh, P., Ye, J., et al. (1994). Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-gamma gene. The Journal of Immunology, 153, 3603–3610.

    CAS  PubMed  Google Scholar 

  • Yung, R., Chang, S., Hemati, N., Johnson, K., & Richardson, B. (1997). Mechanisms of drug induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo. Arthritis and Rheumatism, 40, 1436–1443.

    CAS  PubMed  Google Scholar 

  • Yung, R. L., Quddus, J., Chrisp, C. E., Johnson, K. J., & Richardson, B. C. (1995). Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. The Journal of Immunology, 154, 3025–3035.

    CAS  PubMed  Google Scholar 

  • Yung, R. L., & Richardson, B. C. (1994). Drug-induced lupus. Rheumatic Diseases Clinics of North America, 20, 61–86.

    CAS  PubMed  Google Scholar 

  • Zhao, M., Tang, J., Gao, F., et al. (2010). Hypomethylation of IL-10 and IL-13 promoters in CD4+ T cells of patients with SLE. Journal of Biomedicine and Biotechnology, 2010, 9310–9318.

    Google Scholar 

  • Zhou, Y., & Lu, Q. (2008). DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmunity Reviews, 7, 376–383.

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

Authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Institute for Experimental Medicine (DETAE), Istanbul University, Istanbul, Turkey

    Cem İsmail Küçükali, Merve Çebi & Erdem Tüzün

  2. Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Murat Kürtüncü & Arzu Çoban

Authors
  1. Cem İsmail Küçükali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murat Kürtüncü
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arzu Çoban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Merve Çebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erdem Tüzün
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Erdem Tüzün.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Küçükali, C.İ., Kürtüncü, M., Çoban, A. et al. Epigenetics of Multiple Sclerosis: An Updated Review. Neuromol Med 17, 83–96 (2015). https://doi.org/10.1007/s12017-014-8298-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-014-8298-6

Keywords

Search

Navigation