Single-cell multiome profiling reveals pancreas cell type-specific gene regulatory programs of type 1 diabetes progression [snATAC-seq]

Genomic changes in the pancreas across stages of type 1 diabetes (T1D) progression are poorly understood. In this study, we performed single nucleus RNA-seq and ATAC-seq in whole pancreas samples obtained from non-diabetic, autoantibody-positive, and T1D organ donors. Genomic profiles from 480,154 cells were mapped to 18 pancreatic cell types and sub-types, and we identified altered abundance of beta, delta, immune, and exocrine sub-type cells in T1D progression. Beta, delta, acinar, stellate, and other cell types had marked gene expression changes in both autoantibody-positive and recent-onset T1D together with key epigenomic drivers of altered cell type-specific gene activity. Combining cell type-specific changes in T1D progression with genetic association data revealed cellular pathways of T1D risk, including antigen presentation and interferon signaling in beta cells and metabolism in acinar cells. We identified changes in predicted cell signaling in the pancreas in T1D, including immune-beta signals associated with increased disease risk. Finally, we observed several ligands with altered signaling to beta cells in T1D that had protective effects on beta cell regulation in vitro. These results revealed genomic changes in the pancreas driving T1D risk and progression, observations that form the basis for future therapeutic targets for disease intervention.