Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs driving type 1 diabetes progression

Rebecca L. Melton; Sara Jiménez; Weston S. Elison; Luca Tucciarone; Abigail Howell; Gaowei Wang; Denise A. Berti; Elisha Beebe; Michael Miller; Chun Zeng; Carolyn McGrail; Kennedy VanderStel; Katha Korgaonkar; Ruth M. Elgamal; Hannah M Mummey; Joshua Chiou; Emily N. Griffin; Irina Kusmartseva; Mark A. Atkinson; Sebastian Preißl; Fabian Joachim Theis; Maike Sander; Kyle J. Gaulton

doi:10.1126/sciadv.ady0080

GenomicsScience AdvancesSep 10, 2025

Peer-reviewed journal article

Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs driving type 1 diabetes progression

Rebecca L. Melton iD, Sara Jiménez iD, Weston S. Elison iD, Luca Tucciarone iD, Abigail Howell, Gaowei Wang iD, Denise A. Berti iD, Elisha Beebe iD, Michael Miller iD, Chun Zeng iD, Carolyn McGrail, Kennedy VanderStel, Katha Korgaonkar, Ruth M. Elgamal iD, Hannah M Mummey iD, Joshua Chiou iD, Emily N. Griffin iD, Irina Kusmartseva iD, Mark A. Atkinson iD, Sebastian Preißl iD, Fabian Joachim Theis iD, Maike Sander iD, Kyle J. Gaulton iD

Abstract

Cell type-specific regulatory programs that drive type 1 diabetes (T1D) in the pancreas are poorly understood. Here we performed single nucleus multiomics and spatial transcriptomics in up to 32 non-diabetic (ND), autoantibody-positive (AAB+), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine sub- types. Beta, acinar, and other cell types, and related cellular niches, had altered abundance and gene activity in T1D progression, including distinct pathways altered in AAB+ compared to T1D. We identified epigenomic drivers of gene activity in T1D and AAB+ which, combined with genetic association, revealed causal pathways of T1D risk including antigen presentation in beta cells. Finally, single cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting beta cell regulation. Overall, these results revealed drivers of T1D progression in the pancreas, which form the basis for therapeutic targets for disease prevention.

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