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

Inna Starskaia; Essi Laajala; Toni Grönroos; Taina Härkönen; Sini Junttila; Roosa Kattelus; Henna Kallionpää; Asta Laiho; Veronika Suni; Vallo Tillmann; Riikka Lund; Laura L Elo; Harri Lähdesmäki; Mikael Knip; Ubaid Ullah Kalim; Riitta Lahesmaa

doi:10.1007/s00125-022-05657-x

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

Diabetologia. 2022 May;65(5):844-860. doi: 10.1007/s00125-022-05657-x. Epub 2022 Feb 10.

Authors

Inna Starskaia^{1

2

3}, Essi Laajala^{1

2

3

4}, Toni Grönroos^{1

2}, Taina Härkönen^{5

6}, Sini Junttila^{1

2}, Roosa Kattelus^{1

2}, Henna Kallionpää¹, Asta Laiho^{1

2}, Veronika Suni¹, Vallo Tillmann^{7

8}, Riikka Lund¹, Laura L Elo^{1

2

9}, Harri Lähdesmäki⁴, Mikael Knip^{5

6

10}, Ubaid Ullah Kalim^{11

12}, Riitta Lahesmaa^{13

14

15}

Affiliations

¹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
² InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
³ Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland.
⁴ Department of Computer Science, Aalto University, Espoo, Finland.
⁵ Pediatric Research Center, Children's Hospital, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.
⁶ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁷ Children's Clinic of Tartu University Hospital, Tartu, Estonia.
⁸ Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
⁹ Institute of Biomedicine, University of Turku, Turku, Finland.
¹⁰ Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland.
¹¹ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland. ubaid.ullah@utu.fi.
¹² InFLAMES Research Flagship Center, University of Turku, Turku, Finland. ubaid.ullah@utu.fi.
¹³ Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland. rilahes@utu.fi.
¹⁴ InFLAMES Research Flagship Center, University of Turku, Turku, Finland. rilahes@utu.fi.
¹⁵ Institute of Biomedicine, University of Turku, Turku, Finland. rilahes@utu.fi.

Abstract

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.

Keywords: DNA methylation; Epigenetics; T cells; Type 1 diabetes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoantibodies / genetics
Autoimmunity / genetics
CD8-Positive T-Lymphocytes
Child
CpG Islands
DNA Methylation* / genetics
Diabetes Mellitus, Type 1* / genetics
Epigenesis, Genetic / genetics
Humans
Leukocytes, Mononuclear

Substances

Autoantibodies