Tet2 modulates ER stress responses, β cell death, and autoimmunity in diabetes [snATAC-seq]

In previous studies, we showed that Tet2 controls the responses of beta cells to inflammation in a model of autoimmune Type 1 diabetes, but the specific cell types affected by Tet2 loss in islets was not clear and the molecular mechanisms responsible for the autoimmune responses and beta cell death were unknown. We found that Tet2-deficient islets have fewer islet infiltrating lymphocytes beginning 8-10 weeks after bone marrow transplant, reduced activation of CD8+ T cells, and greater CD8+ T cell repertoire diversity. Transcription factor finding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To confirm the effects of TET2 in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2(TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.