Document Type
Article
Publication Date
11-5-2024
Original Citation
Sokolowski E,
Kursawe R,
Selvam V,
Bhuiyan R,
Thibodeau A,
Zhao C,
Spracklen C,
Ucar D,
Stitzel ML.
Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights. Cell Metab . 2024 Nov 5;36(11):2468-2488.e7.
Keywords
JGM, Humans, Diabetes Mellitus, Type 2, Endoplasmic Reticulum Stress, Islets of Langerhans, Cytokines, Insulin-Secreting Cells, Endoplasmic Reticulum, Male, Polymorphism, Single Nucleotide, Transcriptome, Multiomics
JAX Source
Cell Metab . 2024 Nov 5;36(11):2468-2488.e7.
ISSN
1932-7420
PMID
39383866
DOI
10.1016/j.cmet.2024.09.006
Grant
This study was made possible by generous financial support of the United States Department of Defense (DOD) under award number W81XWH-18-0401 (to M.L.S. and D.U.), American Diabetes Association Pathway to Stop Diabetes Accelerator Award (1-18-ACE-015 to M.L.S.), and National Institutes of Health (NIH) under award numbers R01DK118011 (to M.L.S.), R01AG052608 (to D.U.), and U01AI165452 (to D.U.). C.N.S. was also supported by American Dia- betes Association grant 11-22-JDFPM-06.
Abstract
Endoplasmic reticulum (ER) and inflammatory stress responses contribute to islet dysfunction in type 2 diabetes (T2D). Comprehensive genomic understanding of these human islet stress responses and whether T2D-associated genetic variants modulate them is lacking. Here, comparative transcriptome and epigenome analyses of human islets exposed ex vivo to these stressors revealed 30% of expressed genes and 14% of islet cis-regulatory elements (CREs) as stress responsive, modulated largely in an ER- or cytokine-specific fashion. T2D variants overlapped 86 stress-responsive CREs, including 21 induced by ER stress. We linked the rs6917676-T T2D risk allele to increased islet ER-stress-responsive CRE accessibility and allele-specific β cell nuclear factor binding. MAP3K5, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, MAP3K5 expression correlated inversely with human islet β cell abundance and was elevated in T2D β cells. This study provides genome-wide insights into human islet stress responses and context-specific T2D variant effects.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.