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Epigenetic Modifications and Therapy in Multiple Sclerosis

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Abstract

Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (GWAS), have richened our knowledge of etiopathology of autoimmune diseases (AID) through discovery of genetic patterns. Nonetheless, the precise etiology of autoimmune diseases remains largely unknown. The lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. Although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence. DNA methylation, histone modifications, and microRNA-associated gene expression suppression are the central mechanisms for epigenetic regulations. Multiple sclerosis (MS) is a disorder of the central nervous system (CNS), characterized by both inflammatory and neurodegenerative features. Although studies on epigenetic alterations in MS only began in the past decade, a mounting number of surveys suggest that epigenetic changes may be involved in the initiation and development of MS, probably through bridging the effects of environmental risk factors to genetics. Arming with clear understanding of epigenetic dysregulations underpins development of epigenetic therapies. Identifying agents inhibiting the enzymes controlling epigenetic modifications, particularly DNA methyltransferases and histone deacetylases, will be promising therapeutic tool toward MS. In the article underway, it is aimed to go through the recent progresses, attempting to disclose how epigenetics associates with the pathogenesis of MS and how can be used as therapeutic approach.

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References

  • Akkad, D. A., Hoffjan, S., Petrasch-Parwez, E., Beygo, J., Gold, R., & Epplen, J. T. (2009). Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. Journal of Autoimmunity, 32(2), 110–115. doi:10.1016/j.jaut.2009.01.002.

    Article  CAS  PubMed  Google Scholar 

  • Allione, A., Marcon, F., Fiorito, G., Guarrera, S., Siniscalchi, E., Zijno, A., et al. (2015). Novel epigenetic changes unveiled by monozygotic twins discordant for smoking habits. PLoS One, 10(6), e0128265.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arruda, L., Lorenzi, J., Sousa, A., Zanette, D., Palma, P., Panepucci, R., et al. (2015). Autologous hematopoietic SCT normalizes miR-16,-155 and-142-3p expression in multiple sclerosis patients. Bone Marrow Transplantation, 50(3), 380–389.

    Article  CAS  PubMed  Google Scholar 

  • Aslani, S., Mahmoudi, M., Karami, J., Jamshidi, A. R., Malekshahi, Z., & Nicknam, M. H. (2016). Epigenetic alterations underlying autoimmune diseases. Autoimmunity, 49(2), 69–83.

    Article  CAS  Google Scholar 

  • Aung, L. L., Mouradian, M. M., Dhib-Jalbut, S., & Balashov, K. E. (2015). MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a. Journal of Neuroimmunology, 278, 185–189.

    Article  CAS  PubMed  Google Scholar 

  • Bannister, A. J., & Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Research, 21(3), 381–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baranzini, S. E., Mudge, J., van Velkinburgh, J. C., Khankhanian, P., Khrebtukova, I., Miller, N. A., et al. (2010). Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature, 464(7293), 1351–1356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116(2), 281–297.

    Article  CAS  PubMed  Google Scholar 

  • Bos, S. D., Page, C. M., Andreassen, B. K., Elboudwarej, E., Gustavsen, M. W., Briggs, F., et al. (2015). Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. PLoS One, 10(3), e0117403.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Breitling, L. P., Yang, R., Korn, B., Burwinkel, B., & Brenner, H. (2011). Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. The American Journal of Human Genetics, 88(4), 450–457.

    Article  CAS  PubMed  Google Scholar 

  • Brooks, W. H. (2010). X chromosome inactivation and autoimmunity. Clinical Reviews in Allergy and Immunology, 39(1), 20–29.

    Article  PubMed  Google Scholar 

  • Brooks, W. H., Le Dantec, C., Pers, J.-O., Youinou, P., & Renaudineau, Y. (2010). Epigenetics and autoimmunity. Journal of Autoimmunity, 34(3), J207–J219.

    Article  CAS  PubMed  Google Scholar 

  • Calabrese, R., Valentini, E., Ciccarone, F., Guastafierro, T., Bacalini, M. G., Ricigliano, V., et al. (2014). TET2 gene expression and 5-hydroxymethylcytosine level in multiple sclerosis peripheral blood cells. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(7), 1130–1136.

    Article  CAS  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(3), 299–304.

    Article  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(1), 10–21.

    Article  CAS  PubMed  Google Scholar 

  • Cang, S., Lu, Q., Ma, Y., & Liu, D. (2010). Clinical advances in hypomethylating agents targeting epigenetic pathways. Current Cancer Drug Targets, 10(5), 539–545.

    Article  CAS  PubMed  Google Scholar 

  • Cedar, H., & Bergman, Y. (2009). Linking DNA methylation and histone modification: Patterns and paradigms. Nature Reviews Genetics, 10(5), 295–304.

    Article  CAS  PubMed  Google Scholar 

  • Chan, M. W., Chang, C.-B., Tung, C.-H., Sun, J., Suen, J.-L., & Wu, S.-F. (2014). Low-dose 5-aza-2′-deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells. Molecular Medicine, 20(1), 248.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chao, M. J., Ramagopalan, S. V., Herrera, B. M., Lincoln, M. R., Dyment, D. A., Sadovnick, A. D., et al. (2009). Epigenetics in multiple sclerosis susceptibility: Difference in transgenerational risk localizes to the major histocompatibility complex. Human Molecular Genetics, 18(2), 261–266. doi:10.1093/hmg/ddn353.

    Article  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(8), e12132.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Ruijter, A., Van Gennip, A., Caron, H., Kemp, S., & van Kuilenburg, A. (2003). Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochemical Journal, 370, 737–749.

    Article  PubMed  PubMed Central  Google Scholar 

  • De Santis, G., Ferracin, M., Biondani, A., Caniatti, L., Tola, M. R., Castellazzi, M., et al. (2010). Altered miRNA expression in T regulatory cells in course of multiple sclerosis. Journal of Neuroimmunology, 226(1), 165–171.

    Article  PubMed  CAS  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(12), 1252–1259.

    Article  CAS  PubMed  Google Scholar 

  • Ebers, G. C. (2008). Environmental factors and multiple sclerosis. The Lancet Neurology, 7(3), 268–277.

    Article  PubMed  Google Scholar 

  • Ebert, M. S., & Sharp, P. A. (2010). MicroRNA sponges: Progress and possibilities. Rna, 16(11), 2043–2050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429(6990), 457–463.

    Article  CAS  PubMed  Google Scholar 

  • Esteller, M. (2007). Cancer epigenomics: DNA methylomes and histone-modification maps. Nature Reviews Genetics, 8(4), 286–298.

    Article  CAS  PubMed  Google Scholar 

  • Fan, S., & Zhang, X. (2009). CpG island methylation pattern in different human tissues and its correlation with gene expression. Biochemical and Biophysical Research Communications, 383(4), 421–425.

    Article  CAS  PubMed  Google Scholar 

  • Fenoglio, C., Cantoni, C., De Riz, M., Ridolfi, E., Cortini, F., Serpente, M., et al. (2011). Expression and genetic analysis of miRNAs involved in CD4+ cell activation in patients with multiple sclerosis. Neuroscience Letters, 504(1), 9–12.

    Article  CAS  PubMed  Google Scholar 

  • Fenoglio, C., Ridolfi, E., Cantoni, C., De Riz, M., Bonsi, R., Serpente, M., et al. (2013). Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis. Multiple Sclerosis Journal, 19(14), 1938–1942.

    Article  CAS  PubMed  Google Scholar 

  • Fenoglio, C., Ridolfi, E., Galimberti, D., & Scarpini, E. (2012). MicroRNAs as active players in the pathogenesis of multiple sclerosis. International Journal of Molecular Sciences, 13(10), 13227–13239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fetahu, I. S., Höbaus, J., & Kállay, E. (2014). Vitamin D and the epigenome. Frontiers in Physiology, 5, 164. doi:10.3389/fphys.2014.00164.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gandhi, R., Healy, B., Gholipour, T., Egorova, S., Musallam, A., Hussain, M. S., et al. (2013). Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Annals of Neurology, 73(6), 729–740.

    Article  CAS  PubMed  Google Scholar 

  • Ge, Z., Da, Y., Xue, Z., Zhang, K., Zhuang, H., Peng, M., et al. (2013). Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Experimental Neurology, 241, 56–66.

    Article  CAS  PubMed  Google Scholar 

  • Germolec, D., Kono, D. H., Pfau, J. C., & Pollard, K. M. (2012). Animal models used to examine the role of the environment in the development of autoimmune disease: Findings from an NIEHS Expert Panel Workshop. Journal of Autoimmunity, 39(4), 285–293.

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldenberg, M. M. (2012). Multiple sclerosis review. Pharmacy and Therapeutics, 37(3), 175.

    PubMed  PubMed Central  Google Scholar 

  • Goodin, D. S. (2014). The epidemiology of multiple sclerosis: Insights to disease pathogenesis. Handbook of Clinical Neurology, 122, 231–266.

    Article  PubMed  Google Scholar 

  • Graves, M., Benton, M., Lea, R. A., Boyle, M., Tajouri, L., MacArtney-Coxson, D., et al. (2014). Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. Multiple Sclerosis Journal, 20(8), 1033–1041.

    Article  CAS  PubMed  Google Scholar 

  • Grolleau-Julius, A., Ray, D., & Yung, R. L. (2010). The role of epigenetics in aging and autoimmunity. Clinical Reviews in Allergy and Immunology, 39(1), 42–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guerau-de-Arellano, M., Smith, K. M., Godlewski, J., Liu, Y., Winger, R., Lawler, S. E., et al. (2011). Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain, 134(12), 3578–3589.

    Article  PubMed  Google Scholar 

  • Handel, A. E., De Luca, G. C., Morahan, J., Handunnetthi, L., Sadovnick, A. D., Ebers, G. C., et al. (2010). No evidence for an effect of DNA methylation on multiple sclerosis severity at HLA-DRB1* 15 or HLA-DRB5. Journal of Neuroimmunology, 223(1), 120–123.

    Article  CAS  PubMed  Google Scholar 

  • Hansen, T., Skytthe, A., Stenager, E., Petersen, H. C., Bronnum-Hansen, H., & Kyvik, K. O. (2005). Concordance for multiple sclerosis in Danish twins: An update of a nationwide study. Multiple Sclerosis, 11(5), 504–510.

    Article  CAS  PubMed  Google Scholar 

  • Hawkes, C., & Macgregor, A. (2009). Twin studies and the heritability of MS: A conclusion. Multiple Sclerosis, 15(6), 661–667.

    Article  CAS  PubMed  Google Scholar 

  • Hedrich, C. M. (2011). Genetic variation and epigenetic patterns in autoimmunity. Journal of Genetic Syndromes & Gene therapy, 2, 2.

    Article  Google Scholar 

  • Huang, K., & Fan, G. (2010). DNA methylation in cell differentiation and reprogramming: An emerging systematic view. Regenerative Medicine, 5(4), 531–544.

    Article  CAS  PubMed  Google Scholar 

  • Huynh, J. L., & Casaccia, P. (2013). Epigenetic mechanisms in multiple sclerosis: Implications for pathogenesis and treatment. The Lancet Neurology, 12(2), 195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huynh, J. L., Garg, P., Thin, T. H., Yoo, S., Dutta, R., Trapp, B. D., et al. (2014). Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nature Neuroscience, 17(1), 121–130.

    Article  CAS  PubMed  Google Scholar 

  • Ito, K., Lim, S., Caramori, G., Chung, K., Barnes, P., & Adcock, I. (2001). Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. The FASEB Journal, 15(6), 1110–1112.

    CAS  PubMed  Google Scholar 

  • Izumi, K. M., & Kieff, E. D. (1997). The Epstein-Barr virus oncogene product latent membrane protein 1 engages the tumor necrosis factor receptor-associated death domain protein to mediate B lymphocyte growth transformation and activate NF-κB. Proceedings of the National Academy of Sciences, 94(23), 12592–12597.

    Article  CAS  Google Scholar 

  • J van der Star, B., Vogel, Y. S. D., Kipp, M., Puentes, F., Baker, D., & Amor, S. (2012). In vitro and in vivo models of multiple sclerosis. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 11(5), 570–588.

    Google Scholar 

  • Jafari, N., Shaghaghi, H., Mahmoodi, D., Shirzad, Z., Alibeiki, F., Bohlooli, S., et al. (2015). Overexpression of microRNA biogenesis machinery: Drosha, DGCR8 and Dicer in multiple sclerosis patients. Journal of Clinical Neuroscience, 22(1), 200–203.

    Article  CAS  PubMed  Google Scholar 

  • Janson, P. C., Linton, L. B., Bergman, E. A., Marits, P., Eberhardson, M., Piehl, F., et al. (2011). Profiling of CD4+ T cells with epigenetic immune lineage analysis. The Journal of Immunology, 186(1), 92–102.

    Article  CAS  PubMed  Google Scholar 

  • Javan, M.-R., Seyfizadeh, N., Aslani, S., Farhoodi, M., & Babaloo, Z. (2014). Molecular analysis of interleukin-25 exons 1 and 2 and its serum levels in Iranian patients with multiple sclerosis. American Journal of Clinical and Experimental Immunology, 3(2), 91.

    PubMed  PubMed Central  Google Scholar 

  • Jirtle, R. L., & Skinner, M. K. (2007). Environmental epigenomics and disease susceptibility. Nature Reviews Genetics, 8(4), 253–262.

    Article  CAS  PubMed  Google Scholar 

  • Joshi, S., Pantalena, L.-C., Liu, X. K., Gaffen, S. L., Liu, H., Rohowsky-Kochan, C., et al. (2011). 1, 25-Dihydroxyvitamin D3 ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Molecular and Cellular Biology, 31(17), 3653–3669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Junker, A., Hohlfeld, R., & Meinl, E. (2011). The emerging role of microRNAs in multiple sclerosis. Nature Reviews Neurology, 7(1), 56–59.

    Article  CAS  PubMed  Google Scholar 

  • Junker, A., Krumbholz, M., Eisele, S., Mohan, H., Augstein, F., Bittner, R., et al. (2009). MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain, 132(12), 3342–3352.

    Article  PubMed  Google Scholar 

  • Kacperska, M. J., Jastrzebski, K., Tomasik, B., Walenczak, J., Konarska-Krol, M., & Glabinski, A. (2015). Selected extracellular microRNA as potential biomarkers of multiple sclerosis activity—preliminary study. Journal of Molecular Neuroscience, 56(1), 154–163.

    Article  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(10), e7440.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Keller, A., Leidinger, P., Steinmeyer, F., Stähler, C., Franke, A., Hemmrich-Stanisak, G., et al. (2013). Comprehensive analysis of microRNA profiles in multiple sclerosis including next-generation sequencing. Multiple Sclerosis Journal, 20(3), 295–303.

    Article  PubMed  CAS  Google Scholar 

  • Koch, M. W., Metz, L. M., & Kovalchuk, O. (2013). Epigenetics and miRNAs in the diagnosis and treatment of multiple sclerosis. Trends in molecular Medicine, 19(1), 23–30.

    Article  CAS  PubMed  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(1), 51–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laird, P. W. (2010). Principles and challenges of genome-wide DNA methylation analysis. Nature Reviews Genetics, 11(3), 191–203.

    Article  CAS  PubMed  Google Scholar 

  • Lawson, H. A., Cheverud, J. M., & Wolf, J. B. (2013). Genomic imprinting and parent-of-origin effects on complex traits. Nature Reviews Genetics, 14(9), 609–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, H., He, Y., Richardson, W. D., & Casaccia, P. (2009). Two-tier transcriptional control of oligodendrocyte differentiation. Current Opinion in Neurobiology, 19(5), 479–485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, T., Morgan, M. J., Choksi, S., Zhang, Y., Kim, Y.-S., & Liu, Z.-G. (2010). MicroRNAs modulate the noncanonical transcription factor NF-[kappa] B pathway by regulating expression of the kinase IKK [alpha] during macrophage differentiation. Nature Immunology, 11(9), 799–805.

    Article  CAS  PubMed  PubMed Central  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(1), 16–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindberg, R. L., Hoffmann, F., Mehling, M., Kuhle, J., & Kappos, L. (2010). Altered expression of miR-17-5p in CD4+ lymphocytes of relapsing–remitting multiple sclerosis patients. European Journal of Immunology, 40(3), 888–898.

    Article  CAS  PubMed  Google Scholar 

  • Lorenzi, J. C. C., Brum, D. G., Zanette, D. L., de Paula Alves Souza, A., Barbuzano, F. G., dos Santos, A. C., et al. (2012). miR-15a and 16-1 are downregulated in CD4+ T cells of multiple sclerosis relapsing patients. International Journal of Neuroscience, 122(8), 466–471.

    Article  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(9), 6352–6358.

    Article  CAS  PubMed  Google Scholar 

  • Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., et al. (2009). Finding the missing heritability of complex diseases. Nature, 461(7265), 747–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mastronardi, F. G., Noor, A., Wood, D. D., Paton, T., & Moscarello, M. A. (2007a). Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. Journal of Neuroscience Research, 85(9), 2006–2016.

    Article  CAS  PubMed  Google Scholar 

  • Mastronardi, F., Tsui, H., Winer, S., Wood, D., Selvanantham, T., Galligan, C., et al. (2007). Synergy between paclitaxel plus an exogenous methyl donor in the suppression of murine demyelinating diseases. Multiple sclerosis, 13(5), 596–609.

    Article  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. The Journal of Neuroscience, 26(44), 11387–11396.

    Article  CAS  PubMed  Google Scholar 

  • McCarrey, J. R. (2003). Epigenetic mechanisms regulating gene expression. In S. A. Krawetz & D. D. Womble (Eds.), Introduction to bioinformatics (pp. 123–139). Detroit: Springer.

    Google Scholar 

  • Miller, D., Barkhof, F., Montalban, X., Thompson, A., & Filippi, M. (2005). Clinically isolated syndromes suggestive of multiple sclerosis, part I: Natural history, pathogenesis, diagnosis, and prognosis. The Lancet Neurology, 4(5), 281–288.

    Article  PubMed  Google Scholar 

  • Miyazaki, Y., Li, R., Rezk, A., Misirliyan, H., Moore, C., Farooqi, N., et al. (2014). A novel microRNA-132-surtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis. PLoS One, 9(8), e105421.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moore, C. S., Rao, V. T., Durafourt, B. A., Bedell, B. J., Ludwin, S. K., Bar-Or, A., et al. (2013). miR-155 as a multiple sclerosis–relevant regulator of myeloid cell polarization. Annals of Neurology, 74(5), 709–720.

    Article  CAS  PubMed  Google Scholar 

  • Moscarello, M., Brady, G., Fein, D., Wood, D., & Cruz, T. (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(1), 87–99.

    Article  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(1), 146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ngalamika, O., Zhang, Y., Yin, H., Zhao, M., Gershwin, M. E., & Lu, Q. (2012). Epigenetics, autoimmunity and hematologic malignancies: A comprehensive review. Journal of Autoimmunity, 39(4), 451–465.

    Article  CAS  PubMed  Google Scholar 

  • Niller, H. H., Wolf, H., & Minarovits, J. (2009). Epigenetic dysregulation of the host cell genome in Epstein–Barr virus-associated neoplasia. In T. Vincent (Ed.), Seminars in cancer biology (Vol. 19, pp. 158–164). Stockholm: Elsevier.

    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(9), 2703–2721.

    Article  PubMed  PubMed Central  Google Scholar 

  • Oksenberg, J. R., Baranzini, S. E., Sawcer, S., & Hauser, S. L. (2008). The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nature Reviews Genetics, 9(7), 516–526. doi:10.1038/nrg2395.

    Article  CAS  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(7), e6309.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paraboschi, E. M., Soldà, G., Gemmati, D., Orioli, E., Zeri, G., Benedetti, M. D., et al. (2011). Genetic association and altered gene expression of mir-155 in multiple sclerosis patients. International Journal of Molecular Sciences, 12(12), 8695–8712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedre, X., Mastronardi, F., Bruck, W., López-Rodas, G., Kuhlmann, T., & Casaccia, P. (2011). Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. The Journal of Neuroscience, 31(9), 3435–3445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintero-Ronderos, P., & Montoya-Ortiz, G. (2012). Epigenetics and autoimmune diseases. Autoimmune diseases, 2012(2012), 593720. doi:10.1155/2012/593720.

  • Ramagopalan, S. V., Dobson, R., Meier, U. C., & Giovannoni, G. (2010). Multiple sclerosis: Risk factors, prodromes, and potential causal pathways. The Lancet Neurology, 9(7), 727–739.

    Article  PubMed  Google Scholar 

  • Ramagopalan, S. V., Dyment, D. A., Morrison, K. M., Herrera, B. M., DeLuca, G. C., Lincoln, M. R., et al. (2008). Methylation of class II transactivator gene promoter IV is not associated with susceptibility to multiple sclerosis. BMC Medical Genetics, 9(1), 1.

    Article  CAS  Google Scholar 

  • Riley, K. J., Rabinowitz, G. S., Yario, T. A., Luna, J. M., Darnell, R. B., & Steitz, J. A. (2012). EBV and human microRNAs co-target oncogenic and apoptotic viral and human genes during latency. The EMBO Journal, 31(9), 2207–2221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadovnick, A., Bulman, D., & Ebers, G. (1991). Parent-child concordance in multiple sclerosis. Annals of Neurology, 29(3), 252–255.

    Article  CAS  PubMed  Google Scholar 

  • Scaria, V., Hariharan, M., Maiti, S., Pillai, B., & Brahmachari, S. K. (2006). Host-virus interaction: A new role for microRNAs. Retrovirology, 3(1), 68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sellner, J., Kraus, J., Awad, A., Milo, R., Hemmer, B., & Stüve, O. (2011). The increasing incidence and prevalence of female multiple sclerosis—A critical analysis of potential environmental factors. Autoimmunity Reviews, 10(8), 495–502.

    Article  PubMed  Google Scholar 

  • Selmi, C., Leung, P. S., Sherr, D. H., Diaz, M., Nyland, J. F., Monestier, M., et al. (2012a). Mechanisms of environmental influence on human autoimmunity: A national institute of environmental health sciences expert panel workshop. Journal of Autoimmunity, 39(4), 272–284.

    Article  PubMed  Google Scholar 

  • Selmi, C., Lu, Q., & Humble, M. C. (2012b). Heritability versus the role of the environment in autoimmunity. Journal of Autoimmunity, 39(4), 249–252.

    Article  PubMed  Google Scholar 

  • Shen, S., Sandoval, J., Swiss, V. A., Li, J., Dupree, J., Franklin, R. J., et al. (2008). Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neuroscience, 11(9), 1024–1034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shindler, K. S., Ventura, E., Dutt, M., Elliott, P., Fitzgerald, D. C., & Rostami, A. (2010). Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. Journal of Neuro-Ophthalmology, 30(4), 328.

    Article  PubMed  PubMed Central  Google Scholar 

  • Siegel, S. R., Mackenzie, J., Chaplin, G., Jablonski, N. G., & Griffiths, L. (2012). Circulating microRNAs involved in multiple sclerosis. Molecular Biology Reports, 39(5), 6219–6225.

    Article  CAS  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(1), 70–79.

    Article  CAS  PubMed  Google Scholar 

  • Simpson, S., Blizzard, L., Otahal, P., Van der Mei, I., & Taylor, B. (2011). Latitude is significantly associated with the prevalence of multiple sclerosis: A meta-analysis. Journal of Neurology, Neurosurgery & Psychiatry, 2011, 240432.

    Google Scholar 

  • Singhal, N. K., Li, S., Arning, E., Alkhayer, K., Clements, R., Sarcyk, Z., et al. (2015). Changes in methionine metabolism and histone H3 Trimethylation are linked to mitochondrial defects in multiple sclerosis. The Journal of neuroscience, 35(45), 15170–15186.

    Article  CAS  PubMed  Google Scholar 

  • Smith, K. M., Guerau-de-Arellano, M., Costinean, S., Williams, J. L., Bottoni, A., Cox, G. M., et al. (2012). miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. The Journal of Immunology, 189(4), 1567–1576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Søndergaard, H. B., Hesse, D., Krakauer, M., Sørensen, P. S., & Sellebjerg, F. (2013). Differential microRNA expression in blood in multiple sclerosis. Multiple Sclerosis Journal, 19(14), 1849–1857.

    Article  PubMed  CAS  Google Scholar 

  • Tan, J., Cang, S., Ma, Y., Petrillo, R. L., & Liu, D. (2010). Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. Journal of Hematology & Oncology, 3(5), 1–13.

    Google Scholar 

  • Thamilarasan, M., Koczan, D., Hecker, M., Paap, B., & Zettl, U. K. (2012). MicroRNAs in multiple sclerosis and experimental autoimmune encephalomyelitis. Autoimmunity Reviews, 11(3), 174–179.

    Article  CAS  PubMed  Google Scholar 

  • van Steensel, B. (2005). Mapping of genetic and epigenetic regulatory networks using microarrays. Nature Genetics, 37, S18–S24.

    Article  PubMed  CAS  Google Scholar 

  • Waddington, C. H. (1942). Canalization of development and the inheritance of acquired characters. Nature, 150(3811), 563–565.

    Article  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(9), e24604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westerlind, H., Ramanujam, R., Uvehag, D., Kuja-Halkola, R., Boman, M., Bottai, M., et al. (2014). Modest familial risks for multiple sclerosis: A registry-based study of the population of Sweden. Brain, 137(3), 770–778.

    Article  PubMed  PubMed Central  Google Scholar 

  • Willer, C., D, Dyment, Risch, N., Sadovnick, A., Ebers, G., & Canadian Collaborative Study, Group. (2003). Twin concordance and sibling recurrence rates in multiple sclerosis. Proceedings of the National Academy of Sciences, 100(22), 12877–12882. doi:10.1073/pnas.1932604100.

    Article  CAS  Google Scholar 

  • Wu, D., Cerutti, C., Lopez-Ramirez, M. A., Pryce, G., King-Robson, J., Simpson, J. E., et al. (2015). Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-κB activation. Journal of Cerebral Blood Flow and Metabolism, 35(3), 412–423.

    Article  CAS  PubMed  Google Scholar 

  • Xie, L., Li, X.-K., Funeshima-Fuji, N., Kimura, H., Matsumoto, Y., Isaka, Y., et al. (2009). Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. International Immunopharmacology, 9(5), 575–581.

    Article  CAS  PubMed  Google Scholar 

  • Yang, D., Wang, W.-Z., Zhang, X.-M., Yue, H., Li, B., Lin, L., et al. (2014). MicroRNA expression aberration in Chinese patients with relapsing remitting multiple sclerosis. Journal of Molecular Neuroscience, 52(1), 131–137.

    Article  CAS  PubMed  Google Scholar 

  • Ye, F., Chen, Y., Hoang, T., Montgomery, R. L., Zhao, X.-H., Bu, H., et al. (2009). HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interaction. Nature Neuroscience, 12(7), 829–838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yun, M., Wu, J., Workman, J. L., & Li, B. (2011). Readers of histone modifications. Cell Research, 21(4), 564–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, J., Cheng, Y., Cui, W., Li, M., Li, B., & Guo, L. (2014). MicroRNA-155 modulates Th1 and Th17 cell differentiation and is associated with multiple sclerosis and experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 266(1), 56–63.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Z., Zhang, Z.-Y., Wu, Y., & Schluesener, H. (2012). Valproic acid ameliorates inflammation in experimental autoimmune encephalomyelitis rats. Neuroscience, 221, 140–150.

    Article  CAS  PubMed  Google Scholar 

  • Zivadinov, R., Uxa, L., Bratina, A., Bosco, A., Srinivasaraghavan, B., Minagar, A., et al. (2007). HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis. International Review of Neurobiology, 79, 521–535. doi:10.1016/S0074-7742(07)79023-2.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Saeed Aslani

  2. Markey Cancer Center, University of Kentucky, 741 South Limestone St. Biomedical Biological Research Building (BBSRB), 378D, Lexington, KY, 40506, USA

    Naser Jafari

  3. Department of Immunology, Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran

    Mohammad Reza Javan

  4. Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Jafar Karami

  5. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Majid Ahmadi

  6. Department of Pharmacology, School of Medicine, Ardabil University of Medical Science, Ardabil, Iran

    Mahmoud Jafarnejad

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  1. Saeed Aslani
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  2. Naser Jafari
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  3. Mohammad Reza Javan
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Correspondence to Naser Jafari.

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Aslani, S., Jafari, N., Javan, M.R. et al. Epigenetic Modifications and Therapy in Multiple Sclerosis. Neuromol Med 19, 11–23 (2017). https://doi.org/10.1007/s12017-016-8422-x

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