Defining the unique and shared gene regulatory network components of IRE1αandXBP1in β-cells ofNOD mice

Clinical and preclinical evidence suggest that β-cell endoplasmic reticulum stress and dysregulated unfolded protein response (UPR) contribute to type 1 diabetes (T1D) pathogenesis. During stress adaptation, IRE1α, a key UPR sensor, can exhibit pleiotropic roles. Its deletion in β-cells of non-obese diabetic (NOD) mice prior to insulitis (Ire1αβ-/-) confers protection against T1D. However, specific downstream effectors mediating this protective effect remain unknown. Here we show that β-cell-specific deletion of Xbp1, IRE1α’s downstream effector, protects mice against T1D. Histological and single-cell transcriptomic analyses indicate that Xbp1β-/- mice largely phenocopy Ire1αβ-/- mice. Comparative single-cell transcriptome and gene regulatory network analyses in islets of Ire1αβ-/- and Xbp1β-/- mice reveal unique transcriptional networks, biological processes and network regulators not only in β-cells a but other non-islet β-cell as well. Our findings define the role of β-cell IRE1α/XBP1 pathway and identify previously unrecognized networks and regulatory nodes of this pathway in NOD mice.