Document Type
Article
Publication Date
3-20-2026
Original Citation
Rui J,
Kothari M,
Kursawe R,
Barkestani M,
Genosar R,
Clark P,
Stitzel ML,
Herold K.
Tet2 modulates ER stress responses related to β-cell death and autoimmunity in diabetes. iScience. 2026;29(3):114818.
Keywords
JGM
JAX Source
iScience. 2026;29(3):114818.
ISSN
2589-0042
PMID
41782826
DOI
https://doi.org/10.1016/j.isci.2026.114818
Grant
Research reported in this publication was supported by the National Institute of General Medical Sciences of the Na- tional Institutes of Health under award number 1S10OD030363-01A1.
Abstract
We found that beta cells from Tet2-deficient mice were protected from killing in a model of autoimmune Type 1 diabetes, but the mechanism of protection and specific cell types affected by Tet2 loss were unknown. Herein we show that in Tet2-deficient NOD mice transplanted with wild-type bone marrow, there are fewer islet infiltrating lymphocytes beginning 8–10 weeks after transplant, which was seen primarily among CD4+ T-cells. Transcription factor binding 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 determine whether there were similar effects 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.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.