Abstract
The appearance of diabetes-associated autoantibodies is the first detectable sign of the disease process leading to type 1 diabetes (T1D). Evidence suggests that T1D is a heterogenous disease, where the type of antibodies first formed implies subtypes. Here, we leverage longitudinal samples collected from 98 European TRIGR participants (49 children who subsequently presented with T1D, and 49 matched controls), and profile single-cell epigenomics at different time points of disease development. Quantitation of cell and nuclei populations, complemented by analysis of transcriptome and open-chromatin states, indicates robust, early, replicable monocyte lineage differences between cases and controls, suggesting the early emergence of heightened pro-inflammatory cytokine secretion among cases. The order of autoantibody emergence in cases shows variation across lymphoid and myeloid cells, potentially indicating divergence in the cellular immune response. The strong monocytic lineage representation in peripheral blood immune cells before seroconversion and the weaker differential coordination of these gene networks close to clinical diagnosis emphasize the importance of early life as a critical phase in T1D development.
Data availability
Data are stored in the European Genome-phenome Archive (EGA, https://ega-archive.org) under accession code EGAD50000001257. Individual participant data are shared in a de-identified format to protect the identity of the participants. There are no restrictions on who the data can be made available to or for what purpose. Please contact Marja Salonen (marja.salonen@helsinki.fi) to request access. One to six working days is the expected time frame for a response to access requests. The data will be available for 12 months once access has been granted. All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible and are provided with this paper. Source data are provided with this paper.
Code availability
Code used in the analysis are available on GitHub at https://github.com/ChildrensMercyResearchInstitute/trigr.
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Acknowledgements
T.P. holds a Fred and Dee Lyons Endowed Chair in Pediatric Genomic Medicine. Grant support for the study was from Academy of Finland (grant 350455) to M.K. The authors thank the TRIGR Study Group for making the PBMC samples available from the TRIGR children analyzed in this study. The TRIGR study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (grants HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, JDRF and the Commission of the European Communities (specific RTD program “Quality of Life and management of Living Resources”, contract number QLK1-2002-00372 “Diabetes Prevention”) and the EFSD/JDRF/Novo Nordisk Focused Research Grant.
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T.P. and M.K. designed the study, acquired data, analyzed data, and wrote the manuscript. E.G. and T.B. designed and supervised experiments. J.H., A.V., O.V., and M.K. were responsible for sample collection, sample storage, and the clinical information for the children. W.C., J.J.J., B.Y., and S.K. were responsible for bioinformatic analysis. R.M. assisted with manuscript and figure preparation. J.I. was responsible for the HLA genotyping of the participants. J.P.K. was the PI for the TRIGR Data Management Unit. All authors reviewed/edited the manuscript.
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Nature Communications thanks Roberto Mallone and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Pastinen, T., Grundberg, E., Bradley, T. et al. Evolving epigenomics of immune cells at single-nucleus resolution in children en route to type 1 diabetes. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69923-x
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DOI: https://doi.org/10.1038/s41467-026-69923-x
