The cis-regulatory programs of specific cell types in the pancreas that are affected in type 1 diabetes (T1D) are poorly understood. Single cell technology enables detailed interrogation of genomic profiles of cell types within a heterogeneous tissue, and when applied to samples across disease states can reveal cell type-specific changes in disease. In this study we applied single nucleus RNA-seq (snRNA-seq) and single nucleus ATAC-seq (snATAC-seq) , as well as paired multiome (snRNA-seq+snATAC-seq) , to cryopreserved whole pancreas samples from 34 donors including 13 control, 9 T1D autoantibody positive (Aab+) , 7 early T1D (1< yr) and 5 late T1D donors in the nPOD biorepository. Clustering of 313,078 gene expression and 342,863 accessible chromatin profiles after extensive processing and filtering resolved pancreatic endocrine, exocrine, immune, stellate, glial and endothelial cell types, as well as known and novel cell sub-types for example REG1A+ acinar cells and MUC5b+ ductal cells. There were marked changes in the abundance of many cell types and sub-types across disease states, including a significant reduction in beta cells and increase in immune cell populations in T1D compared to control. Differential analysis of gene expression and cis-regulatory element (cCRE) activity in each cell type revealed changes in early and late T1D, as well as in T1D Aab+. In beta cells, 2 and 2,177 genes and 1,080 and 9,177 cCREs had differential activity in early and late T1D, respectively, and early and late T1D genes in beta cells were enriched for distinct molecular processes related to interferon gamma signaling and cell death. Intersecting differential beta cell cCREs with comprehensive T1D genetic fine-mapping revealed 13 T1D signals where candidate variants mapped in a differential beta cell cRE of which were proximal to a differentially expressed gene, such as at the GLIS3 locus. Together these results provide insight into the role of cis-regulatory programs in beta cells and other pancreatic cell types in T1D.


R.Melton: None. S.Preissl: None. M.Sander: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated. E.Beebe: None. C.Zeng: None. M.T.Miller: None. G.Wang: None. C.Mcgrail: None. H.Mummey: None. I.Kusmartseva: None. M.A.Atkinson: None.


Ruth Kirschstein Institutional National Research Service Award T32 (GM008666) National Institutes of Health (DK120429)

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