Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies. Consequent hyperglycemia is requiring lifelong insulin replacement therapy. T1DM is caused by the interaction of multiple environmental and genetic factors. The integrations of environments and genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. T1DM has increased several-fold over the past half century. Such a short time indicates involvement of environment factors and excludes genetic changes. This review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus.

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruska 87 100 00 Prague 10 Czech Republic

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Sharp S.A., Weedon M.N., Hagopian W.A., Oram R.A. Clinical and research uses of genetic risk scores in type 1 diabetes. Curr. Opin. Genet. Dev. 2018;50:96–102. doi: 10.1016/j.gde.2018.03.009. PubMed DOI PMC

Nyaga D.M., Vickers M.H., Jefferies C., Perry J.K., O’Sullivan J.M. The genetic architecture of type 1 diabetes mellitus. Mol. Cell. Endocrinol. 2018;477:70–80. doi: 10.1016/j.mce.2018.06.002. PubMed DOI

Abbas A.K., Lichtman A.H., Pillai S. Cellular and Molecular Immunology. 7th ed. Elsevier Saunders; Philadelphia, PA, USA: 2012.

Cerna M. Genetics of autoimmune diabetes mellitus. Wien. Med. Wochenschr. 2008;158:2–12. doi: 10.1007/s10354-007-0448-0. PubMed DOI

Rewers M., Ludvigsson J. Environmental risk factors for type 1 diabetes. Lancet. 2016;387:2340–2348. doi: 10.1016/S0140-6736(16)30507-4. PubMed DOI PMC

Paun A., Yau C., Danska J.S. The influence of the microbiome on type 1 diabetes. J. Immunol. 2017;198:590–595. doi: 10.4049/jimmunol.1601519. PubMed DOI

Bach J.F. The hygiene hypothesis in autoimmunity: The role of pathogens and commensals. Nat. Rev. Immunol. 2018;18:105–120. doi: 10.1038/nri.2017.111. PubMed DOI

Sharif K., Watad A., Coplan L., Amital H., Shoenfeld Y., Afek A. Psychological stress and type 1 diabetes mellitus: What is the link? Expert Rev. Clin. Immunol. 2018;14:1081–1088. doi: 10.1080/1744666X.2018.1538787. PubMed DOI

Allis C.D., Jenuwein T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 2016;17:487–500. doi: 10.1038/nrg.2016.59. PubMed DOI

Rose N.R., Klose R.J. Understanding the relationship between DNA methylation and histone lysine methylation. Biochim. Biophys. Acta. 2014;1839:1362–1372. doi: 10.1016/j.bbagrm.2014.02.007. PubMed DOI PMC

Garcia-Gonzalez E., Escamilla-Del-Arenal M., Arzate-Mejia R., Recillas-Targa F. Chromatin remodeling effects on enhancer activity. Cell. Mol. Life Sci. 2016;73:2897–2910. doi: 10.1007/s00018-016-2184-3. PubMed DOI PMC

Ruiz-Hernandez A., Kuo C.-C., Rentero-Garrido P., Tang W.-Y., Redon J., Ordovas J.M., Navas-Acien A., Tellez-Plaza M. Environmental chemicals and DNA methylation in adults: A systematic review of the epidemiologic evidence. Clin. Epigenet. 2015;7:55. doi: 10.1186/s13148-015-0055-7. PubMed DOI PMC

Gaine M.E., Chatterjee S., Abel T. Sleep deprivation and the epigenome. Front. Neural Circuits. 2018;12:14. doi: 10.3389/fncir.2018.00014. PubMed DOI PMC

Yu G., Wu Q., Gao Y., Chen M., Yang M. The epigenetics of aging in invertebrates. Int. J. Mol. Sci. 2019;20:4535. doi: 10.3390/ijms20184535. PubMed DOI PMC

Sapienza C., Issa J.P. Diet, nutrition, and cancer epigenetics. Annu. Rev. Nutr. 2016;36:665–681. doi: 10.1146/annurev-nutr-121415-112634. PubMed DOI

Picascia A., Grimaldi V., Pignalosa O., De Pascale M.R., Schiano C., Napoli C. Epigenetic control of autoimmune diseases: From bench to bedside. Clin. Immunol. 2015;157:1–15. doi: 10.1016/j.clim.2014.12.013. PubMed DOI

Taudt A., Colomé-Tatché M., Johannes F. Genetic sources of population epigenomic variation. Nat. Rev. Genet. 2016;17:319–332. doi: 10.1038/nrg.2016.45. PubMed DOI

Surace A.E.A., Hedrich C.M. The role of epigenetics in autoimmune/inflammatory disease. Front. Immunol. 2019;10:1525. doi: 10.3389/fimmu.2019.01525. PubMed DOI PMC

Klose R.J., Bird A.P. Genomic DNA methylation: The mark and its mediators. Trends Biochem. Sci. 2006;31:89–97. doi: 10.1016/j.tibs.2005.12.008. PubMed DOI

Weber M., Hellmann I., Stadler M.B., Ramos L., Pääbo S., Rebhan M., Schübeler D. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 2007;39:457–466. doi: 10.1038/ng1990. PubMed DOI

Shen H., Qiu C., Li J., Tian Q., Deng H.-W. Characterization of the DNA methylome and its interindividual variation in human peripheral blood monocytes. Epigenomics. 2013;5:255–269. doi: 10.2217/epi.13.18. PubMed DOI PMC

Majumder P., Boss J.M. DNA methylation dysregulates and silences the HLA-DQ locus by altering chromatin architecture. Genes Immun. 2011;12:291–299. doi: 10.1038/gene.2010.77. PubMed DOI PMC

Zajacová M. Ph.D. Thesis. Charles University, Third Faculty of Medicine; Vinohrady, Czech Republic: 2018. Regulation of HLA Class II Genes Expression.

Xiang Z., Yang Y., Chang C., Lu Q. The epigenetic mechanism for discordance of autoimmunity in monozygotic twins. J. Autoimmun. 2017;83:43–50. doi: 10.1016/j.jaut.2017.04.003. PubMed DOI

Rakyan V.K., Beyan H., Down T.A., Hawa M.I., Maslau S., Aden D., Daunay A., Busato F., Mein C.A., Manfras B., et al. Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet. 2011;7:1002300. doi: 10.1371/journal.pgen.1002300. PubMed DOI PMC

Stefan M., Zhang W., Concepcion E., Yi Z., Tomer Y. DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J. Autoimmun. 2014;50:33–37. doi: 10.1016/j.jaut.2013.10.001. PubMed DOI PMC

Elboudwarej E., Cole M., Briggs F.B.S., Fouts A., Fain P.R., Quach H., Quach D., Sinclair E., Criswell L.A., Lane J.A., et al. Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins. J. Autoimmun. 2016;68:23–29. doi: 10.1016/j.jaut.2015.12.003. PubMed DOI PMC

Paul D., Teschendorff A.E., Dang M.A., Lowe R., Hawa M.I., Ecker S., Beyan H., Cunningham S., Fouts A.R., Ramelius A., et al. Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat. Commun. 2016;7:13555. doi: 10.1038/ncomms13555. PubMed DOI PMC

Disanto G., Vcelakova J., Pakpoor J., Elangovan R.I., Sumnik Z., Ulmannova T., Ebers G.C., Ramagopalan S.V., Stechová K. DNA methylation in monozygotic quadruplets affected by type 1 diabetes. Diabetologia. 2013;56:2093–2095. doi: 10.1007/s00125-013-2972-3. PubMed DOI

Zajacova M., Kotrbova-Kozak A., Cepek P., Cerna M. Differences in promoter DNA methylation and mRNA expression of individual alleles of the HLA class II DQA1 gene. Immunol. Lett. 2015;167:147–154. doi: 10.1016/j.imlet.2015.08.006. PubMed DOI

Cepek P., Zajacova M., Kotrbova-Kozak A., Silhova E., Cerna M. DNA methylation and mRNA expression of HLA-DQA1 alleles in type 1 diabetes mellitus. Immunology. 2016;148:150–159. doi: 10.1111/imm.12593. PubMed DOI PMC

Li Y., Zhao M., Hou C., Liang G., Yang L., Tan Y., Wang Z., Yin H., Zhou Z., Lu Q. Abnormal DNA methylation in CD4+ T cells from people with latent autoimmune diabetes in adults. Diabetes Res. Clin. Pract. 2011;94:242–248. doi: 10.1016/j.diabres.2011.07.027. PubMed DOI

Redondo M.J., Steck A.K., Pugliese A. Genetics of type 1 diabetes. Pediatr. Diabetes. 2018;19:346–353. doi: 10.1111/pedi.12597. PubMed DOI PMC

Fradin D., Le Fur S., Mille C., Naoui N., Groves C., Zelenika D., McCarthy M.I., Lathrop M., Bougnères P. Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. PLoS ONE. 2012;7:0036278. doi: 10.1371/journal.pone.0036278. PubMed DOI PMC

Rui J., Deng S., Lebastchi J., Clark P.L., Usmani-Brown S., Herold K.C. Methylation of insulin DNA in response to proinflammatory cytokines during the progression of autoimmune diabetes in NOD mice. Diabetologia. 2016;59:1021–1029. doi: 10.1007/s00125-016-3897-4. PubMed DOI PMC

Husseiny M.I., Kuroda A., Kaye A.N., Nair I., Kandeel F., Ferreri K. Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PLoS ONE. 2012;7:0047942. doi: 10.1371/journal.pone.0047942. PubMed DOI PMC

Akirav E.M., Lebastchi J., Galvan E.M., Henegariu O., Akirav M., Ablamunits V., Lizardi P.M., Herold K.C. Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc. Natl. Acad. Sci. USA. 2011;108:19018–19023. doi: 10.1073/pnas.1111008108. PubMed DOI PMC

Fisher M.M., Watkins R.A., Blum J., Evans-Molina C., Chalasani N., DiMeglio L.A., Mather K.J., Tersey S.A., Mirmira R.G. Elevations in circulating methylated and unmethylated preproinsulin DNA in new-onset type 1 diabetes. Diabetes. 2015;64:3867–3872. doi: 10.2337/db15-0430. PubMed DOI PMC

Olsen J.A., Kenna L.A., Spelios M.G., Hessner M.J., Akirav E.M. Circulating differentially methylated amylin DNA as a biomarker of β-cell loss in type 1 diabetes. PLoS ONE. 2016;11:0152662. doi: 10.1371/journal.pone.0152662. PubMed DOI PMC

Belot M.P., Fradin D., Mai N., Le Fur S., Zélénika D., Kerr-Conte J., Pattou F., Lucas B., Bougnères P. CpG methylation changes within the IL2RA promoter in type 1 diabetes of childhood onset. PLoS ONE. 2013;8:e68093. doi: 10.1371/journal.pone.0068093. PubMed DOI PMC

Chen B., Sun L., Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. J. Autoimmun. 2017;83:31–42. doi: 10.1016/j.jaut.2017.03.009. PubMed DOI

Knip M., Siljander H. The role of the intestinal microbiota in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 2016;12:154–167. doi: 10.1038/nrendo.2015.218. PubMed DOI

Davis-Richardson A.G., Triplett E.W. A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia. 2015;58:1386–1393. doi: 10.1007/s00125-015-3614-8. PubMed DOI PMC

Gowher H., Jeltsch A. Mammalian DNA methyltransferases: New discoveries and open questions. Biochem. Soc. Trans. 2018;46:1191–1202. doi: 10.1042/BST20170574. PubMed DOI PMC

Suzuki K., Luo Y. Histone acetylation and the regulation of major histocompatibility class II gene expression. Adv. Protein Chem. Struct. Biol. 2017;106:71–111. PubMed

Miao F., Smith D.D., Zhang L., Min A., Feng W., Natarajan R. Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation. Diabetes. 2008;57:3190–3198. doi: 10.2337/db08-0645. PubMed DOI PMC

Miao F., Chen Z., Zhang L., Liu Z., Wu X., Yuan Y.C., Natarajan R. Profiles of epigenetic histone post-translational modifications at type 1 diabetes susceptible genes. J. Biol. Chem. 2012;287:16335–16345. doi: 10.1074/jbc.M111.330373. PubMed DOI PMC

Miao F., Gonzalo I.G., Lanting L., Natarajan R. In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions. J. Biol. Chem. 2004;279:18091–18097. doi: 10.1074/jbc.M311786200. PubMed DOI

Miao F., Wu X., Zhang L., Yuan Y.C., Riggs A.D., Natarajan R. Genome-wide analysis of histone lysine methylation variations caused by diabetic conditions in human monocytes. J. Biol. Chem. 2007;282:13854–13863. doi: 10.1074/jbc.M609446200. PubMed DOI

Chen S.S., Jenkins A.J., Majewski H. Elevated plasma prostaglandins and acetylated histone in monocytes in type 1 diabetes patients. Diabet. Med. 2009;26:182–186. doi: 10.1111/j.1464-5491.2008.02658.x. PubMed DOI

Liu X.Y., Xu J.F. Reduced histone H3 acetylation in CD4+ T lymphocytes: Potential mechanism of latent autoimmune diabetes in adults. Dis. Markers. 2015;2015:285125. doi: 10.1155/2015/285125. PubMed DOI PMC

Holoch D., Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat. Rev. Genet. 2015;16:71–84. doi: 10.1038/nrg3863. PubMed DOI PMC

Svoboda P. Renaissance of mammalian endogenous RNAi. FEBS Lett. 2014;588:2550–2556. doi: 10.1016/j.febslet.2014.05.030. PubMed DOI

Hezova R., Slaby O., Faltejskova P., Mikulkova Z., Buresova I., Raja M., Hodek J., Ovesna J., Michalek J. MicroRNA-342, microRNA-191 and microRNA-510 are differentially expressed in T regulatory cells of type 1 diabetic patients. Cell. Immunol. 2010;260:70–74. doi: 10.1016/j.cellimm.2009.10.012. PubMed DOI

de Jong V.M., van der Slik A.R., Laban S., van ‘t Slot R., Koeleman B.P.C., Zaldumbide A., Roep B.O. Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes. Genes Immun. 2016;17:342–348. doi: 10.1038/gene.2016.29. PubMed DOI

Sebastiani G., Grieco F.A., Spagnuolo I., Galleri L., Cataldo D., Dotta F. Increased expression of microRNA miR-326 in type 1 diabetic patients with ongoing islet autoimmunity. Diabetes Metab. Res. Rev. 2011;27:862–866. doi: 10.1002/dmrr.1262. PubMed DOI

Salas-Perez F., Codner E., Valencia E., Pizarro C., Carrasco E., Perez-Bravo F. MicroRNAs miR-21a and miR-93 are down regulated in peripheral blood mononuclear cells (PBMCs) from patients with type 1 diabetes. Immunobiology. 2013;218:733–737. doi: 10.1016/j.imbio.2012.08.276. PubMed DOI

Wang S., Wan X., Ruan Q. The microRNA-21 in autoimmune diseases. Int. J. Mol. Sci. 2016;17:864. doi: 10.3390/ijms17060864. PubMed DOI PMC

Yang M., Ye L., Wang B., Gao J., Liu R., Hong J., Wang W., Gu W., Ning G. Decreased miR-146 expression in peripheral blood mononuclear cells is correlated with ongoing islet autoimmunity in type 1 diabetes patients. J. Diabetes. 2015;7:158–165. doi: 10.1111/1753-0407.12163. PubMed DOI

Zheng Y., Wang Z., Zhou Z. miRNAs: Novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes. Cell. Mol. Immunol. 2017;14:488–496. doi: 10.1038/cmi.2017.7. PubMed DOI PMC

Garo L.P., Murugaiyan G. Contribution of microRNAs to autoimmune diseases. Cell. Mol. Life. Sci. 2016;73:2041–2051. doi: 10.1007/s00018-016-2167-4. PubMed DOI PMC

Ruan Q., Wang T., Kameswaran V., Wei Q., Johnson D.S., Matschinsky F., Shi W., Chen Y.H. The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic β cell death. Proc. Natl. Acad. Sci. USA. 2011;108:12030–12035. doi: 10.1073/pnas.1101450108. PubMed DOI PMC

Jerram S.T., Dang M.N., Leslie R.D. The role of epigenetics in type 1 diabetes. Curr. Diabetes Rep. 2017;17:89. doi: 10.1007/s11892-017-0916-x. PubMed DOI PMC

Zullo A., Sommese L., Nicoletti G., Donatelli F., Mancini F.P., Napoli C. Epigenetics and type 1 diabetes: Mechanisms and translational applications. Transl. Res. 2017;185:85–93. doi: 10.1016/j.trsl.2017.05.002. PubMed DOI