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Epigenetics for Clinicians from the Perspective of Pediatric Rheumatic Diseases

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Epigenetics is the study of inherited phenotype changes that do not involve in alteration of DNA sequence. Epigenetic regulation can be examined under three main headings and study methodologies for all three will be discussed: DNA methylation is the addition of a methyl (CH3) group to DNA, histone modifications is a covalent post-translational modification of histones and non-coding RNAs are a group of functional RNA molecules that is copied from DNA but not converted into proteins. Epigenetic changes are being increasingly studied in the pathogenesis of most diseases including autoimmune and autoinflammatory diseases to shed light on the different phenotypes and disease courses. We have aimed to review the basic concepts in epigenetic studies and summarize the data for epigenetics in autoimmune and autoinflammatory rheumatic diseases.

Recent Findings

Recent studies have assessed DNA hypomethylation in interferon-regulated genes in autoimmune diseases and in inflammatory pathways in systemic autoinflammatory diseases (SAIDs). Abnormal histone acetylation and methylation have been shown to be important in autoimmune diseases which was proven via effective targeted treatment trials against these pathways in mice models. miRNAs have an important role in the pathogenesis, and also, they can be used as diagnostic biomarkers in SAIDs (i.e., FMF, Behcet’s disease) together with autoimmune diseases. Although the number of studies has increased over the years in parallel with the increase of interest in this field, we await further studies to improve the understanding and management of pediatric rheumatic diseases.

Summary

Epigenetic studies in pediatric rheumatic diseases have enabled us to gain new information about disease pathogenesis, clinical heterogeneity, and prognosis. Further studies will help us define new diagnostic, prognostic, and therapeutic goals for rheumatic diseases.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Holliday R, Grigg GW. DNA methylation and mutation. Mutat Res - Fundam Mol Mech Mutagen. 1993;285:61–7. https://doi.org/10.1016/0027-5107(93)90052-H.

    Article  CAS  Google Scholar 

  2. Zemach A, McDaniel IE, Silva P, Zilberman D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science (80-). 2010;328:916–9. https://doi.org/10.1126/science.1186366.

    Article  CAS  Google Scholar 

  3. Zemach A, Zilberman D. Evolution of eukaryotic DNA methylation and the pursuit of safer sex. Curr Biol. 2010;20. https://doi.org/10.1016/j.cub.2010.07.007.

  4. Li E, Zhang Y. DNA methylation in mammals. Cold Spring Harb Perspect Biol. 2014;6. https://doi.org/10.1101/cshperspect.a019133.

  5. Mohandas T, Sparkes RS, Shapiro LJ. Reactivation of an inactive human X chromosome: Evidence for X inactivation by DNA methylation. Science (80-). 1981;211:393–6. https://doi.org/10.1126/science.6164095.

    Article  CAS  Google Scholar 

  6. Greenberg MVC, Bourc’his D. The diverse roles of DNA methylation in mammalian development and disease. Nat Rev. Mol Cell Biol. 2019;20:590–607. https://doi.org/10.1038/s41580-019-0159-6.

    Article  CAS  PubMed  Google Scholar 

  7. Suzuki MM, Bird A. DNA methylation landscapes: Provocative insights from epigenomics. Nat Rev. Genet. 2008;9:465–76. https://doi.org/10.1038/nrg2341.

    Article  CAS  PubMed  Google Scholar 

  8. Clements EG, Mohammad HP, Leadem BR, Easwaran H, Cai Y, Van Neste L, et al. DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res. 2012;40:4334–46. https://doi.org/10.1093/nar/gks031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lim DHK, Maher ER. DNA methylation: a form of epigenetic control of gene expression. Obstet Gynaecol. 2010;12:37–42. https://doi.org/10.1576/toag.12.1.037.27556.

    Article  Google Scholar 

  10. Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011;25:1010–22. https://doi.org/10.1101/gad.2037511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lyko F. The DNA methyltransferase family: A versatile toolkit for epigenetic regulation. Nat Rev. Genet. 2018;19:81–92. https://doi.org/10.1038/nrg.2017.80.

    Article  CAS  PubMed  Google Scholar 

  12. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57. https://doi.org/10.1016/S0092-8674(00)81656-6.

    Article  CAS  PubMed  Google Scholar 

  13. Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30:733–50. https://doi.org/10.1101/gad.276568.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bhutani N, Burns DM, Blau HM. DNA demethylation dynamics. Cell. 2011;146:866–72. https://doi.org/10.1016/j.cell.2011.08.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science (80-). 2011;333:1303–7. https://doi.org/10.1126/science.1210944.

    Article  CAS  Google Scholar 

  16. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science (80-). 2011;333:1300–3. https://doi.org/10.1126/science.1210597.

    Article  CAS  Google Scholar 

  17. • Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013;502:472–9. https://doi.org/10.1038/nature12750.b. The authors describe perfectly the DNA demethylation enzymes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurdyukov S, Bullock M. DNA methylation analysis: Choosing the right method. Biology (Basel). 2016;5. https://doi.org/10.3390/biology5010003.

  19. Kuo KC, McCune RA, Gehrke CW, Midgett R, Ehrlich M. Quantitative reversed-phase high performance liquid chromatographic determination of major and modified deoxyribonucleosides in DNA. Nucleic Acids Res. 1980;8:4763–76. https://doi.org/10.1093/nar/8.20.4763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu Z, Wu J, Xie Z, Liu S, Fan-Havard P, Huang THM, et al. Quantification of regional DNA methylation by liquid chromatography/tandem mass spectrometry. Anal Biochem. 2009;391:106–13. https://doi.org/10.1016/j.ab.2009.05.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kremer D, Metzger S, Kolb-Bachofen V, Kremer D. Quantitative measurement of genome-wide DNA methylation by a reliable and cost-efficient enzyme-linked immunosorbent assay technique. Anal Biochem. 2012;422:74–8. https://doi.org/10.1016/j.ab.2011.11.033.

    Article  CAS  PubMed  Google Scholar 

  22. Mohsen K, Johansson S, Ekström TJ, Karimi M. Using LUMA: a luminometric-based assay for global DNA-methylation. Epigenetics. 2006;1:45–8. https://doi.org/10.4161/epi.1.1.2587.

    Article  Google Scholar 

  23. Karimi M, Johansson S, Stach D, Corcoran M, Grandér D, Schalling M, et al. LUMA (LUminometric Methylation Assay)-a high throughput method to the analysis of genomic DNA methylation. Exp Cell Res. 2006;312:1989–95. https://doi.org/10.1016/j.yexcr.2006.03.006.

    Article  CAS  PubMed  Google Scholar 

  24. Schumacher A, Kapranov P, Kaminsky Z, Flanagan J, Assadzadeh A, Yau P, et al. Microarray-based DNA methylation profiling: technology and applications. Nucleic Acids Res. 2006;34:528–42. https://doi.org/10.1093/nar/gkj461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li Y, Tollefsbol TO. DNA methylation detection: bisulfite genomic sequencing analysis. Methods Mol Biol. 2011;791:11–21. https://doi.org/10.1007/978-1-61779-316-5_2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Angelini F, Pagano F, Bordin A, Milan M, Chimenti I, Peruzzi M, et al. The impact of environmental factors in influencing epigenetics related to oxidative states in the cardiovascular System. Oxid Med Cell Longev. 2017;2017. https://doi.org/10.1155/2017/2712751.

  27. Akbaba T, Balcı-Peynircioğlu B. Potential impacts of gut microbiota on immune system related diseases: current studies and future challenges. Acta Medica Cordoba. 2018;49:31–7.

    Google Scholar 

  28. Mizugaki M, Yamaguchi T, Ishiwata S, Shindo H, Hishinuma T, Nozaki S, et al. Alteration of DNA methylation levels in MRL lupus mice. Clin Exp Immunol. 1997;110:265–9. https://doi.org/10.1111/j.1365-2249.1997.tb08326.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou Y, Lu Q. DNA methylation in T cells from idiopathic lupus and drug-induced lupus patients. Autoimmun Rev. 2008;7:376–83. https://doi.org/10.1016/j.autrev.2008.03.003.

    Article  CAS  PubMed  Google Scholar 

  30. 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;33:1665–73. https://doi.org/10.1002/art.1780331109.

    Article  CAS  PubMed  Google Scholar 

  31. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1998;9:765–75. https://doi.org/10.1016/s1074-7613(00)80642-1.

    Article  CAS  PubMed  Google Scholar 

  32. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182:259–73. https://doi.org/10.4049/jimmunol.182.1.259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ngalamika O, Liang G, Zhao M, Yu X, Yang Y, Yin H, et al. Peripheral whole blood FOXP3 TSDR methylation: a potential marker in severity assessment of autoimmune diseases and chronic infections. Immunol Invest. 2015;44:126–36. https://doi.org/10.3109/08820139.2014.938165.

    Article  CAS  PubMed  Google Scholar 

  34. Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010;20:170–9. https://doi.org/10.1101/gr.100289.109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhao M, Liu S, Luo S, Wu H, Tang M, Cheng W, et al. DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun. 2014;54:127–36. https://doi.org/10.1016/j.jaut.2014.07.002.

    Article  CAS  PubMed  Google Scholar 

  36. Coit P, Jeffries M, Altorok N, Dozmorov MG, Koelsch KA, Wren JD, et al. Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naive CD4+ T cells from lupus patients. J Autoimmun. 2013;43:78–84. https://doi.org/10.1016/j.jaut.2013.04.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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;75:1998–2006. https://doi.org/10.1136/annrheumdis-2015-208410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Imgenberg-Kreuz J, Carlsson Almlof J, Leonard D, Alexsson A, Nordmark G, Eloranta ML, et al. DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2018;77:736–43. https://doi.org/10.1136/annrheumdis-2017-212379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Coit P, Renauer P, Jeffries MA, Merrill JT, McCune WJ, Maksimowicz-McKinnon K, et al. Renal involvement in lupus is characterized by unique DNA methylation changes in naive CD4+ T cells. J Autoimmun. 2015;61:29–35. https://doi.org/10.1016/j.jaut.2015.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Renauer P, Coit P, Jeffries MA, Merrill JT, McCune WJ, Maksimowicz-McKinnon K, et al. DNA methylation patterns in naive CD4+ T cells identify epigenetic susceptibility loci for malar rash and discoid rash in systemic lupus erythematosus. Lupus Sci Med. 2015;2:e000101. https://doi.org/10.1136/lupus-2015-000101.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li Y, Zhao M, Yin H, Gao F, Wu X, Luo Y, et al. Overexpression of the growth arrest and DNA damage-induced 45alpha gene contributes to autoimmunity by promoting DNA demethylation in lupus T cells. Arthritis Rheum. 2010;62:1438–47. https://doi.org/10.1002/art.27363.

    Article  CAS  PubMed  Google Scholar 

  42. Li Y, Huang C, Zhao M, Liang G, Xiao R, Yung S, et al. A possible role of HMGB1 in DNA demethylation in CD4+ T cells from patients with systemic lupus erythematosus. Clin Dev Immunol. 2013;2013:206298. https://doi.org/10.1155/2013/206298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao M, Sun Y, Gao F, Wu X, Tang J, Yin H, et al. Epigenetics and SLE: RFX1 downregulation causes CD11a and CD70 overexpression by altering epigenetic modifications in lupus CD4+ T cells. J Autoimmun. 2010;35:58–69. https://doi.org/10.1016/j.jaut.2010.02.002.

    Article  CAS  PubMed  Google Scholar 

  44. Zhao M, Wang J, Liao W, Li D, Li M, Wu H, et al. Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus. J Autoimmun. 2016;69:64–73. https://doi.org/10.1016/j.jaut.2016.03.001.

    Article  CAS  PubMed  Google Scholar 

  45. Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, et al. The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity. 2015;42:613–26. https://doi.org/10.1016/j.immuni.2015.03.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fali T, Le Dantec C, Thabet Y, Jousse S, Hanrotel C, Youinou P, et al. DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus. Autoimmunity. 2014;47:265–71. https://doi.org/10.3109/08916934.2013.826207.

    Article  CAS  PubMed  Google Scholar 

  47. Nakkuntod J, Avihingsanon Y, Mutirangura A, Hirankarn N. Hypomethylation of LINE-1 but not Alu in lymphocyte subsets of systemic lupus erythematosus patients. Clin Chim Acta. 2011;412:1457–61. https://doi.org/10.1016/j.cca.2011.04.002.

    Article  CAS  PubMed  Google Scholar 

  48. Scharer CD, Blalock EL, Mi T, Barwick BG, Jenks SA, Deguchi T, et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol. 2019;20:1071–82. https://doi.org/10.1038/s41590-019-0419-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kirectepe AK, Kasapcopur O, Arisoy N, Celikyapi Erdem G, Hatemi G, Ozdogan H, et al. Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever. BMC Med Genet. 2011;12:105. https://doi.org/10.1186/1471-2350-12-105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vento-Tormo R, Álvarez-Errico D, Garcia-Gomez A, Hernández-Rodríguez J, Buján S, Basagaña M, et al. DNA demethylation of inflammasome-associated genes is enhanced in patients with cryopyrin-associated periodic syndromes. J Allergy Clin Immunol. 2017;139:202–211.e6. https://doi.org/10.1016/j.jaci.2016.05.016.

    Article  CAS  PubMed  Google Scholar 

  51. Hughes T, Ture-Ozdemir F, Alibaz-Oner F, Coit P, Direskeneli H, Sawalha AH. Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behcet’s disease. Arthritis Rheumatol. 2014;66:1648–58. https://doi.org/10.1002/art.38409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hu N, Qiu X, Luo Y, Yuan J, Li Y, Lei W, et al. Abnormal histone modification patterns in lupus CD4+ T cells. J Rheumatol. 2008;35:804–10.

    CAS  PubMed  Google Scholar 

  53. Zhang Z, Song L, Maurer K, Petri MA, Sullivan KE. Global H4 acetylation analysis by ChIP-chip in systemic lupus erythematosus monocytes. Genes Immun. 2010;11:124–33. https://doi.org/10.1038/gene.2009.66.

    Article  CAS  PubMed  Google Scholar 

  54. Dai Y, Zhang L, Hu C, Zhang Y. Genome-wide analysis of histone H3 lysine 4 trimethylation by ChIP-chip in peripheral blood mononuclear cells of systemic lupus erythematosus patients. Clin Exp Rheumatol. 2010;28:158–68.

    CAS  PubMed  Google Scholar 

  55. Zhao H, Wang L, Luo H, Li QZ, Zuo X. TNFAIP3 downregulation mediated by histone modification contributes to T cell dysfunction in systemic lupus erythematosus. Rheumatol. 2017;56:835–43. https://doi.org/10.1093/rheumatology/kew508.

    Article  CAS  Google Scholar 

  56. Sullivan KE, Suriano A, Dietzmann K, Lin J, Goldman D, Petri MA. The TNFalpha locus is altered in monocytes from patients with systemic lupus erythematosus. Clin Immunol. 2007;123:74–81. https://doi.org/10.1016/j.clim.2006.12.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Apostolidis SA, Rauen T, Hedrich CM, Tsokos GC, Crispin JC. Protein phosphatase 2A enables expression of interleukin 17 (IL-17) through chromatin remodeling. J Biol Chem. 2013;288:26775–84. https://doi.org/10.1074/jbc.M113.483743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hedrich CM, Rauen T, Apostolidis SA, Grammatikos AP, Rodriguez Rodriguez N, Ioannidis C, et al. Stat3 promotes IL-10 expression in lupus T cells through trans-activation and chromatin remodeling. Proc Natl Acad Sci U S A. 2014;111:13457–62. https://doi.org/10.1073/pnas.1408023111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wardowska A, Komorniczak M, Bullo-Piontecka B, Debska-Slizien MA, Pikula M. Transcriptomic and epigenetic alterations in dendritic cells correspond with chronic kidney disease in lupus nephritis. Front Immunol. 2019;10:2026. https://doi.org/10.3389/fimmu.2019.02026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rother N, Pieterse E, Lubbers J, Hilbrands L, van der Vlag J. Acetylated histones in apoptotic microparticles drive the formation of neutrophil extracellular traps in active lupus nephritis. Front Immunol. 2017;8:1136. https://doi.org/10.3389/fimmu.2017.01136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hofmann SR, Kubasch AS, Ioannidis C, Rösen-Wolff A, Girschick HJ, Morbach H, et al. Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1β expression and release. Clin Immunol. 2015;161:300–7. https://doi.org/10.1016/j.clim.2015.09.013.

    Article  CAS  PubMed  Google Scholar 

  62. Pan W, Zhu S, Yuan M, Cui H, Wang L, Luo X, et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol. 2010;184:6773–81. https://doi.org/10.4049/jimmunol.0904060.

    Article  CAS  PubMed  Google Scholar 

  63. Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothe F, Simion A, et al. Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009;39:1608–18. https://doi.org/10.1002/eji.200838509.

    Article  CAS  PubMed  Google Scholar 

  64. Stagakis E, Bertsias G, Verginis P, Nakou M, Hatziapostolou M, Kritikos H, et al. Identification of novel microRNA signatures linked to human lupus disease activity and pathogenesis: miR-21 regulates aberrant T cell responses through regulation of PDCD4 expression. Ann Rheum Dis. 2011;70:1496–506. https://doi.org/10.1136/ard.2010.139857.

    Article  CAS  PubMed  Google Scholar 

  65. Liao Z, Ye Z, Xue Z, Wu L, Ouyang Y, Yao C, et al. Identification of renal long non-coding RNA RP11-2B6.2 as a positive regulator of type I interferon signaling pathway in lupus nephritis. Front Immunol. 2019;10:975. https://doi.org/10.3389/fimmu.2019.00975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu Y, Zhang F, Ma J, Zhang X, Wu L, Qu B, et al. Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus. Arthritis Res Ther. 2015;17:131. https://doi.org/10.1186/s13075-015-0632-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Latsoudis H, Mashreghi MF, Grün JR, Chang HD, Stuhlmüller B, Repa A, et al. Differential expression of mir-4520a associated with pyrin mutations in familial Mediterranean fever (FMF). J Cell Physiol. 2017;232:1326–36. https://doi.org/10.1002/jcp.25602.

    Article  CAS  PubMed  Google Scholar 

  68. Koga T, Migita K, Sato T, Sato S, Umeda M, Nonaka F, et al. MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase gamma pathway. Rheumatol. 2018;57:718–26. https://doi.org/10.1093/rheumatology/kex451.

    Article  CAS  Google Scholar 

  69. Akkaya-Ulum YZ, Balci-Peynircioglu B, Karadag O, Eroglu FK, Kalyoncu U, Kiraz S, et al. Alteration of the microRNA expression profile in familial Mediterranean fever patients. Clin Exp Rheumatol. 2017;35(Suppl 1):90–4.

    PubMed  Google Scholar 

  70. Amarilyo G, Pillar N, Ben-Zvi I, Weissglas-Volkov D, Zalcman J, Harel L, et al. Analysis of microRNAs in familial Mediterranean fever. PLoS One. 2018;13:e0197829. https://doi.org/10.1371/journal.pone.0197829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Akkaya-Ulum ZY, Tavukcuoglu Z, Batu ED, Akbaba TH, Sonmez HS, Balci-Peynircioglu B. et al. Possible regulatory effects of miRNAs in the pathogenesis of systemic auto inflammatory diseases, from the perspective of familial Mediterranean fever. 10th Congress of International Society of Systemic Auto Inflammatory Diseases (ISSAID). Pediatr Rheumatol. 2019;17:18. https://doi.org/10.1186/s12969-019-0313-x.

  72. Oner T, Yenmis G, Tombulturk K, Cam C, Kucuk OS, Yakicier MC, et al. Association of pre-miRNA-499 rs3746444 and pre-miRNA-146a rs2910164 polymorphisms and susceptibility to Behcet’s disease. Genet Test Mol Biomarkers. 2015;19:424–30. https://doi.org/10.1089/gtmb.2015.0016.

    Article  CAS  PubMed  Google Scholar 

  73. Ibrahim W, Sakr BR, Obaya E, Ghonem H. MicroRNA-146a expression and microRNA-146a rs2910164 polymorphism in Behcet’s disease patients. Clin Rheumatol. 2019;38:397–402. https://doi.org/10.1007/s10067-018-4191-2.

    Article  CAS  PubMed  Google Scholar 

  74. Zhou Q, Hou S, Liang L, Li X, Tan X, Wei L, et al. MicroRNA-146a and Ets-1 gene polymorphisms in ocular Behcet’s disease and Vogt-Koyanagi-Harada syndrome. Ann Rheum Dis. 2014;73:170–6. https://doi.org/10.1136/annrheumdis-2012-201627.

    Article  CAS  PubMed  Google Scholar 

  75. Yu H, Liu Y, Bai L, Kijlstra A, Yang P. Predisposition to Behcet’s disease and VKH syndrome by genetic variants of miR-182. J Mol Med. 2014;92:961–7. https://doi.org/10.1007/s00109-014-1159-9.

    Article  CAS  PubMed  Google Scholar 

  76. Qi J, Hou S, Zhang Q, Liao D, Wei L, Fang J, et al. A functional variant of pre-miRNA-196a2 confers risk for Behcet’s disease but not for Vogt-Koyanagi-Harada syndrome or AAU in ankylosing spondylitis. Hum Genet. 2013;132:1395–404. https://doi.org/10.1007/s00439-013-1346-8.

    Article  CAS  PubMed  Google Scholar 

  77. Lee KK, Workman JL. Histone acetyltransferase complexes: One size does not fit all. Nat Rev. Mol Cell Biol. 2007;8:284–95. https://doi.org/10.1038/nrm2145.

    Article  CAS  PubMed  Google Scholar 

  78. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95. https://doi.org/10.1038/cr.2011.22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Oliver SS, Denu JM. Dynamic interplay between histone H3 modifications and protein interpreters: emerging evidence for a “histone language”. ChemBioChem. 2011;12:299–307. https://doi.org/10.1002/cbic.201000474.

    Article  CAS  PubMed  Google Scholar 

  80. Sterner DE, Berger SL. Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev. 2000;64:435–59. https://doi.org/10.1128/mmbr.64.2.435-459.2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yan C, Boyd DD. Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol Cell Biol. 2006;26:6357–71. https://doi.org/10.1128/MCB.00311-06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. 2005;25:552–63. https://doi.org/10.1183/09031936.05.00117504.

    Article  CAS  PubMed  Google Scholar 

  83. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6. https://doi.org/10.1101/cshperspect.a018713.

  84. Greer EL, Shi Y. Histone methylation: A dynamic mark in health, disease and inheritance. Nat Rev. Genet. 2012;13:343–57. https://doi.org/10.1038/nrg3173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hyun K, Jeon J, Park K, Kim J. Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017;49. https://doi.org/10.1038/emm.2017.11.

  86. Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat Rev. Mol Cell Biol. 2005;6:838–49. https://doi.org/10.1038/nrm1761.

    Article  CAS  PubMed  Google Scholar 

  87. Casciello F, Windloch K, Gannon F, Lee JS. Functional role of G9a histone methyltransferase in cancer. Front Immunol. 2015;6. https://doi.org/10.3389/fimmu.2015.00487.

  88. Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012;48:491–507. https://doi.org/10.1016/j.molcel.2012.11.006.

    Article  CAS  PubMed  Google Scholar 

  89. Rossetto D, Avvakumov N, Côté J. Histone phosphorylation: a chromatin modification involved in diverse nuclear events. Epigenetics. 2012;7:1098–108. https://doi.org/10.4161/epi.21975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shiio Y, Eisenman RN. Histone sumoylation is associated with transcriptional repression. Proc Natl Acad Sci U S A. 2003;100:13225–30. https://doi.org/10.1073/pnas.1735528100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stanley JS, Griffin JB, Zempleni J. Biotinylation of histones in human cells. Eur J Biochem. 2001;268:5424–9. https://doi.org/10.1046/j.0014-2956.2001.02481.x.

    Article  CAS  PubMed  Google Scholar 

  92. Lara E, Calvanese V, Fernandez AF, Fraga MF. Techniques to study DNA methylation and histone modification. Epigenetic Asp. Chronic Dis., Springer London. 2011:21–39. https://doi.org/10.1007/978-1-84882-644-1_2.

  93. Song N, Liu J, An S, Nishino T, Hishikawa Y, Koji T. Immunohistochemical analysis of histone H3 modifications in germ cells during mouse spermatogenesis. Acta Histochem Cytochem. 2011;44:183–90. https://doi.org/10.1267/ahc.11027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Collas P. The current state of chromatin immunoprecipitation. Mol Biotechnol. 2010;45:87–100. https://doi.org/10.1007/s12033-009-9239-8.

    Article  CAS  PubMed  Google Scholar 

  95. • Sidoli S, Bhanu NV, Karch KR, Wang X, Garcia BA. Complete workflow for analysis of histone post-translational modifications using bottom-up mass spectrometry: from histone extraction to data analysis. J Vis Exp. 2016;2016. https://doi.org/10.3791/54112. The authors explained the workflow of the MS-based method for histone post-transcriptional modification studies.

  96. Benedetti R, Conte M, Altucci L. Targeting histone deacetylases in diseases: where are we? Antioxidants Redox Signal. 2015;23:99–126. https://doi.org/10.1089/ars.2013.5776.

    Article  CAS  Google Scholar 

  97. Mishra N, Reilly CM, Brown DR, Ruiz P, Gilkeson GS. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest. 2003;111:539–52. https://doi.org/10.1172/JCI16153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hu N, Long H, Zhao M, Yin H, Lu Q. Aberrant expression pattern of histone acetylation modifiers and mitigation of lupus by SIRT1-siRNA in MRL/lpr mice. Scand J Rheumatol. 2009;38:464–71. https://doi.org/10.3109/03009740902895750.

    Article  CAS  PubMed  Google Scholar 

  99. Shu J, Li L, Zhou LB, Qian J, Fan ZD, Zhuang LL, et al. IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors. Oncotarget. 2017;8:47184–94. https://doi.org/10.18632/oncotarget.17586.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Choi EW, Song JW, Ha N, Choi YI, Kim S. CKD-506, a novel HDAC6-selective inhibitor, improves renal outcomes and survival in a mouse model of systemic lupus erythematosus. Sci Rep. 2018;8:17297. https://doi.org/10.1038/s41598-018-35602-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ren J, Catalina MD, Eden K, Liao X, Read KA, Luo X, et al. Selective histone deacetylase 6 inhibition normalizes B cell activation and germinal center formation in a model of systemic lupus erythematosus. Front Immunol. 2019;10:2512. https://doi.org/10.3389/fimmu.2019.02512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Ren J, Liao X, Vieson MD, Chen M, Scott R, Kazmierczak J, et al. Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses. Clin Exp Immunol. 2018;191:19–31. https://doi.org/10.1111/cei.13046.

    Article  CAS  PubMed  Google Scholar 

  103. Carta S, Tassi S, Semino C, Fossati G, Mascagni P, Dinarello CA, et al. Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules. Blood. 2006;108:1618–26. https://doi.org/10.1182/blood-2006-03-014126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med. 2005;11:1–15. https://doi.org/10.2119/2006-00005.Dinarello.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bodar EJ, Simon A, van der Meer JW. Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes. Mol Med. 2011;17:363–8. https://doi.org/10.2119/molmed.2011.00039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Palazzo AF, Lee ES. Non-coding RNA: What is functional and what is junk? Front Genet. 2015;5. https://doi.org/10.3389/fgene.2015.00002.

  107. Hombach S, Kretz M. Non-coding RNAs: Classification, biology and functioning. Adv Exp Med Biol. 2016;937:3–17. https://doi.org/10.1007/978-3-319-42059-2_1.

    Article  CAS  PubMed  Google Scholar 

  108. MacFarlane L-A, Murphy RP. MicroRNA: biogenesis, function and role in cancer. Curr Genomics. 2010;11:537–61. https://doi.org/10.2174/138920210793175895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kozomara A, Birgaoanu M, Griffiths-Jones S. MiRBase: from microRNA sequences to function. Nucleic Acids Res. 2019;47:D155–62. https://doi.org/10.1093/nar/gky1141.

    Article  CAS  PubMed  Google Scholar 

  110. Hashimoto Y, Akiyama Y, Yuasa Y. Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. PLoS One. 2013;8. https://doi.org/10.1371/journal.pone.0062589.

  111. • Gu W, Xu Y, Xie X, Wang T, Ko JH, Zhou T. The role of RNA structure at 5′ untranslated region in microRNA-mediated gene regulation. RNA. 2014;20:1369–75. https://doi.org/10.1261/rna.044792.114. Authors identified the role of the 5′ untranslated region as a previously under-appreciated epigenetic mechanism in gene regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vasudevan S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev. RNA. 2012;3:311–30. https://doi.org/10.1002/wrna.121.

    Article  CAS  PubMed  Google Scholar 

  113. Yao RW, Wang Y, Chen LL. Cellular functions of long noncoding RNAs. Nat Cell Biol. 2019;21:542–51. https://doi.org/10.1038/s41556-019-0311-8.

    Article  CAS  PubMed  Google Scholar 

  114. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–50. https://doi.org/10.1101/gr.3715005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Cabili M, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A, et al. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011;25:1915–27. https://doi.org/10.1101/gad.17446611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Brockdorff N, Ashworth A, Kay GF, McCabe VM, Norris DP, Cooper PJ, et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 1992;71:515–26. https://doi.org/10.1016/0092-8674(92)90519-I.

    Article  CAS  PubMed  Google Scholar 

  117. Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41. https://doi.org/10.1038/sj.onc.1206928.

    Article  CAS  PubMed  Google Scholar 

  118. Brannan CI, Dees EC, Ingram RS, Tilghman SM. The product of the H19 gene may function as an RNA. Mol Cell Biol. 1990;10:28–36. https://doi.org/10.1128/mcb.10.1.28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Forero DA, González-Giraldo Y, Castro-Vega LJ, Barreto GE. qPCR-based methods for expression analysis of miRNAs. Biotechniques. 2019;67:192–9. https://doi.org/10.2144/btn-2019-0065.

    Article  CAS  PubMed  Google Scholar 

  120. Hunt EA, Broyles D, Head T, Deo SK. MicroRNA Detection: Current Technology and Research Strategies. Annu Rev. Anal Chem. 2015;8:217–37. https://doi.org/10.1146/annurev-anchem-071114-040343.

    Article  CAS  Google Scholar 

  121. • Biscontin A, Casara S, Cagnin S, Tombolan L, Rosolen A, Lanfranchi G, et al. New miRNA labeling method for bead-based quantification. BMC Mol Biol. 2010;11. https://doi.org/10.1186/1471-2199-11-44. The authors investigated and defined a new and easy method for miRNA studies.

  122. Balci-Peynircioglu B, Akkaya-Ulum YZ, Akbaba TH, Tavukcuoglu Z. Potential of miRNAs to predict and treat inflammation from the perspective of familial Mediterranean fever. Inflamm Res. 2019;68:905–13. https://doi.org/10.1007/s00011-019-01272-6.

    Article  CAS  PubMed  Google Scholar 

  123. Feng Y, Hu X, Zhang Y, Zhang D, Li C, Zhang L. Methods for the study of long noncoding RNA in cancer cell signaling. Methods Mol Biol. 2014;1165:115–43. https://doi.org/10.1007/978-1-4939-0856-1_10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Cao M, Zhao J, Hu G. Genome-wide methods for investigating long noncoding RNAs. Biomed Pharmacother. 2019;111:395–401. https://doi.org/10.1016/j.biopha.2018.12.078.

    Article  CAS  PubMed  Google Scholar 

  125. Mongelli A, Martelli F, Farsetti A, Gaetano C. The dark that matters: Long noncoding RNAs as master regulators of cellular metabolism in noncommunicable diseases. Front Physiol. 2019;10. https://doi.org/10.3389/fphys.2019.00369.

  126. Tang Y, Zhou T, Yu X, Xue Z, Shen N. The role of long non-coding RNAs in rheumatic diseases. Nat Rev. Rheumatol. 2017;13:657–69. https://doi.org/10.1038/nrrheum.2017.162.

    Article  CAS  PubMed  Google Scholar 

  127. Zheng X, Zhang Y, Yue P, Liu L, Wang C, Zhou K, et al. Diagnostic significance of circulating miRNAs in systemic lupus erythematosus. PLoS One. 2019;14:e0217523. https://doi.org/10.1371/journal.pone.0217523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ye H, Wang X, Wang L, Chu X, Hu X, Sun L, et al. Full high-throughput sequencing analysis of differences in expression profiles of long noncoding RNAs and their mechanisms of action in systemic lupus erythematosus. Arthritis Res Ther. 2019;21:70. https://doi.org/10.1186/s13075-019-1853-7.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Wang Y, Chen S, Chen S, Du J, Lin J, Qin H, et al. Long noncoding RNA expression profile and association with SLEDAI score in monocyte-derived dendritic cells from patients with systematic lupus erythematosus. Arthritis Res Ther. 2018;20:138. https://doi.org/10.1186/s13075-018-1640-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Akkaya-Ulum ZY, Tavukcuoglu Z, Akbaba TH, Yılmaz E, Balci-Peynircioglu B. miR-197 regulates inflammation in monocytes and synovial fibroblasts by targeting IL1R1.10th Congress of International Society of Systemic Auto Inflammatory Diseases (ISSAID). Pediatr Rheumatol. 2019:17. https://doi.org/10.1186/s12969-019-0313-x.

  131. Hortu HO, Karaca E, Sozeri B, Gulez N, Makay B, Gunduz C, et al. Evaluation of the effects of miRNAs in familial Mediterranean fever. Clin Rheumatol. 2019;38:635–43. https://doi.org/10.1007/s10067-017-3914-0.

    Article  PubMed  Google Scholar 

  132. Zhou Q, Xiao X, Wang C, Zhang X, Li F, Zhou Y, et al. Decreased microRNA-155 expression in ocular Behcet’s disease but not in Vogt Koyanagi Harada syndrome. Invest Ophthalmol Vis Sci. 2012;53:5665–74. https://doi.org/10.1167/iovs.12-9832.

    Article  CAS  PubMed  Google Scholar 

  133. Ahmadi M, Yousefi M, Abbaspour-Aghdam S, Dolati S, Aghebati-Maleki L, Eghbal-Fard S, et al. Disturbed Th17/Treg balance, cytokines, and miRNAs in peripheral blood of patients with Behcet’s disease. J Cell Physiol. 2019;234:3985–94. https://doi.org/10.1002/jcp.27207.

    Article  CAS  PubMed  Google Scholar 

  134. Na SY, Park MJ, Park S, Lee ES. MicroRNA-155 regulates the Th17 immune response by targeting Ets-1 in Behcet’s disease. Clin Exp Rheumatol. 2016;34:S56–63.

    PubMed  Google Scholar 

  135. Kolahi S, Farajzadeh MJ, Alipour S, Abhari A, Farhadi J, Bahavarnia N, et al. Determination of mir-155 and mir-146a expression rates and its association with expression level of TNF-alpha and CTLA4 genes in patients with Behcet’s disease. Immunol Lett. 2018;204:55–9. https://doi.org/10.1016/j.imlet.2018.10.012.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study is a part of the E­RARE­3 project (INSAID, grant 003037603) and funded by the Technical and Scientific Research Council of Turkey (TUBITAK), grant number: 315S096.

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  1. Banu Balci-Peynircioglu and Seza Ozen are joint senior authors on this work.

Authors and Affiliations

  1. Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Tayfun Hilmi Akbaba & Banu Balci-Peynircioglu

  2. Department of Paediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Erdal Sag & Seza Ozen

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  1. Tayfun Hilmi Akbaba
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THA wrote the manuscript and made figures. ES wrote the manuscript. BBP and SO reviewed and edited the manuscript.

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Akbaba, T.H., Sag, E., Balci-Peynircioglu, B. et al. Epigenetics for Clinicians from the Perspective of Pediatric Rheumatic Diseases. Curr Rheumatol Rep 22, 46 (2020). https://doi.org/10.1007/s11926-020-00912-9

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