Early DNA methylation changes in children developing beta cell autoimmunity at a young age

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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Diabetologia, Volume 65, issue 5
Aims/hypothesis: Type 1 diabetes is a chronic autoimmune disease of complex aetiology, including a potential role for epigenetic regulation. Previous epigenomic studies focused mainly on clinically diagnosed individuals. The aim of the study was to assess early DNA methylation changes associated with type 1 diabetes already before the diagnosis or even before the appearance of autoantibodies. Methods: Reduced representation bisulphite sequencing (RRBS) was applied to study DNA methylation in purified CD4+ T cell, CD8+ T cell and CD4−CD8− cell fractions of 226 peripheral blood mononuclear cell samples longitudinally collected from seven type 1 diabetes-specific autoantibody-positive individuals and control individuals matched for age, sex, HLA risk and place of birth. We also explored correlations between DNA methylation and gene expression using RNA sequencing data from the same samples. Technical validation of RRBS results was performed using pyrosequencing. Results: We identified 79, 56 and 45 differentially methylated regions in CD4+ T cells, CD8+ T cells and CD4−CD8− cell fractions, respectively, between type 1 diabetes-specific autoantibody-positive individuals and control participants. The analysis of pre-seroconversion samples identified DNA methylation signatures at the very early stage of disease, including differential methylation at the promoter of IRF5 in CD4+ T cells. Further, we validated RRBS results using pyrosequencing at the following CpG sites: chr19:18118304 in the promoter of ARRDC2; chr21:47307815 in the intron of PCBP3; and chr14:81128398 in the intergenic region near TRAF3 in CD4+ T cells. Conclusions/interpretation: These preliminary results provide novel insights into cell type-specific differential epigenetic regulation of genes, which may contribute to type 1 diabetes pathogenesis at the very early stage of disease development. Should these findings be validated, they may serve as a potential signature useful for disease prediction and management. Graphical abstract: [Figure not available: see fulltext.]
Funding Information: Open Access funding provided by University of Turku (UTU) including Turku University Central Hospital. R Lahesmaa was supported by the Academy of Finland (AoF) (grants 292335, 294337, 319280, 31444, 319280, 329277, 331790) and Business Finland, and grants from JDRF, the Novo Nordisk Foundation (grant NNF19OC0057218), the Sigrid Jusélius Foundation (SJF), the Jane and Aatos Erkko Foundation, the Finnish Diabetes Foundation and the Finnish Cancer Foundation. R Lahesmaa, HL and MK were supported by the AoF Centre of Excellence in Molecular Systems Immunology and Physiology Research (2012–2017), grant 250114 and grant 292482. VT was supported by the Estonian Research Council (grant PRG1428). LLE reports grants from the European Research Council (ERC) (677943), the European Union’s Horizon 2020 research and innovation programme (955321), the AoF (296801, 310561, 314443, 329278, 335434 and 335611) and the SJF. Our research is also supported by the University of Turku Graduate School (UTUGS), Biocenter Finland and the InFLAMES Flagship Programme of the AoF (decision number: 337530). IS was supported by the Turku Doctoral Programme of Molecular Medicine (TuDMM) and the Finnish Diabetes Research Foundation. EL was supported by the TuDMM, the Finnish Cultural Foundation, and the Kyllikki and Uolevi Lehikoinen Foundation. TG was supported by the Academy of Finland (grant 340231). Funding Information: We are grateful to the families for their participation in the DIABIMMUNE study and the clinical personnel for excellent collaboration, work with the families and collection of the samples for the study. We thank M. Hakkarainen and S. Heinonen (Turku Bioscience Centre, University of Turku, Finland) for their excellent technical help. We acknowledge the Turku Bioscience Centre’s core facility, the Finnish Functional Genomics Centre (FFGC), supported by Biocenter Finland, for their assistance. We also acknowledge the Finnish Centre for Scientific Computing (CSC), Elixir Finland and the Aalto Science-IT project for computational resources. The graphical abstract was created with BioRender. Publisher Copyright: © 2022, The Author(s).
DNA methylation, Epigenetics, T cells, Type 1 diabetes
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Starskaia, I, Laajala, E, Grönroos, T, Härkönen, T, Junttila, S, Kattelus, R, Kallionpää, H, Laiho, A, Suni, V, Tillmann, V, Lund, R, Elo, L L, Lähdesmäki, H, Knip, M, Kalim, U U & Lahesmaa, R 2022, ' Early DNA methylation changes in children developing beta cell autoimmunity at a young age ', Diabetologia, vol. 65, no. 5, pp. 844-860 . https://doi.org/10.1007/s00125-022-05657-x