Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel
{"title":"多组学人类胰岛内质网和细胞因子应激反应图谱提供 2 型糖尿病遗传学见解","authors":"Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel","doi":"10.1016/j.cmet.2024.09.006","DOIUrl":null,"url":null,"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 <em>ex vivo</em> to these stressors revealed 30% of expressed genes and 14% of islet <em>cis</em>-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. <em>MAP3K5</em>, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, <em>MAP3K5</em> 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.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"12 1","pages":""},"PeriodicalIF":27.7000,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights\",\"authors\":\"Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel\",\"doi\":\"10.1016/j.cmet.2024.09.006\",\"DOIUrl\":null,\"url\":null,\"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 <em>ex vivo</em> to these stressors revealed 30% of expressed genes and 14% of islet <em>cis</em>-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. <em>MAP3K5</em>, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, <em>MAP3K5</em> 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.\",\"PeriodicalId\":9840,\"journal\":{\"name\":\"Cell metabolism\",\"volume\":\"12 1\",\"pages\":\"\"},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-10-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell metabolism\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cmet.2024.09.006\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cmet.2024.09.006","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights
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.
期刊介绍:
Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others.
Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.