Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights
Eishani Kumar Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel
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. • Genome-wide comparative human islet ER/cytokine stress response maps • T2D variants overlap 86 stress-responsive cis -regulatory elements (CREs) • Variant-to-function links between T2D variant rs6917676, MAP3K5 , and islet apoptosis • Risk allele increased ER-stress-induced CRE accessibility and MAP3K5 -mediated death This multi-omic study dissects the genome-wide effects of ER stress and pro-inflammatory cytokines on human islet transcriptional regulatory networks and motivates variant-to-function studies linking the rs6917676 T2D risk allele to enhanced ER-stress-responsive MAP3K5- mediated β cell apoptosis. The findings suggest that MAP3K5 inhibitors (e.g., selonsertib) could therapeutically reduce stress-induced β cell apoptosis.