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

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Item Type:	Article
Title:	Single-cell multiome and spatial profiling reveals pancreas cell type-specific gene regulatory programs of type 1 diabetes progression
Creators Name:	Melton, Rebecca, Jimenez, Sara, Elison, Weston, Tucciarone, Luca, Howell, Abigail, Wang, Gaowei, Berti, Denise, Beebe, Elisha, Miller, Michael, Zeng, Chun, McGrail, Carolyn, VanderStel, Kennedy, Korgaonkar, Katha, Elgamal, Ruth, Mummey, Hannah, Chiou, Joshua, Griffin, Emily, Kusmartseva, Irina, Atkinson, Mark, Preissl, Sebastian, Theis, Fabian J., Sander, Maike and Gaulton, Kyle J.
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 nondiabetic (ND), autoantibody-positive (AAB(+)), and T1D pancreas donors. Genomic profiles from 853,005 cells mapped to 12 pancreatic cell types, including multiple exocrine subtypes. β, 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 β cells. Last, single-cell and spatial profiles together revealed widespread changes in cell-cell signaling in T1D including signals affecting β cell regulation. Overall, these results revealed drivers of T1D in the pancreas, which form the basis for therapeutic targets for disease prevention.
Keywords:	Autoantibodies, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Insulin-Secreting Cells, Pancreas, Single-Cell Analysis, Transcriptome, Type 1 Diabetes Mellitus
Source:	Science Advances
ISSN:	2375-2548
Publisher:	American Association for the Advancement of Science
Volume:	11
Number:	37
Page Range:	eady0080
Date:	12 September 2025
Additional Information:	Accession "GSE273594", "GSE273597" and "GSE273598" are currently private and are scheduled to be released on Sep 19, 2025.
Official Publication:	https://doi.org/10.1126/sciadv.ady0080
PubMed:	View item in PubMed
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE273594 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE273597 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE273598 External Dataset https://www.gaultonlab.org/pages/T1D-pancreas-genomics/ External Dataset https://doi.org/10.5281/zenodo.15832080 Software https://github.com/Gaulton-Lab/nPOD Software https://github.com/theislab/spatial_pancreas Software https://edoc.mdc-berlin.de/25699/ Dataset https://edoc.mdc-berlin.de/25700/ Dataset

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