Defining the unique and shared gene regulatory network components of IRE1aandXBP1in ß-cells ofNOD mice

Clinical and preclinical evidence suggest that ß-cell endoplasmic reticulum stress and dysregulated unfolded protein response (UPR) contribute to type 1 diabetes (T1D) pathogenesis. During stress adaptation, IRE1a, a key UPR sensor, can exhibit pleiotropic roles. Its deletion in ß-cells of non-obese diabetic (NOD) mice prior to insulitis (Ire1aß-/-) confers protection against T1D. However, specific downstream effectors mediating this protective effect remain unknown. Here we show that ß-cell-specific deletion of Xbp1, IRE1a's downstream effector, protects mice against T1D. Histological and single-cell transcriptomic analyses indicate that Xbp1ß-/- mice largely phenocopy Ire1aß-/- mice. Comparative single-cell transcriptome and gene regulatory network analyses in islets of Ire1aß-/- and Xbp1ß-/- mice reveal unique transcriptional networks, biological processes and network regulators not only in ß-cells a but other non-islet ß-cell as well. Our findings define the role of ß-cell IRE1a/XBP1 pathway and identify previously unrecognized networks and regulatory nodes of this pathway in NOD mice. Overall design: Single cell RNA-seq of 5-week-old Xbp1fl/fl (WT) and Xbp1ß-/- (KO) mice were done with n = 2 per group