1/1
3 files

A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus

figure
posted on 20.08.2020 by Ada Admin, Robert N. Bone, Olufunmilola Oyebamiji, Sayali Talware, Sharmila Selvaraj, Preethi Krishnan, Farooq Syed, Huanmei Wu, Carmella Evans-Molina
The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. In parallel, we generated an RNA-sequencing dataset from human islets treated with brefeldin A (BFA), a known GA stress inducer. Overlapping the T1D and T2D groups with the BFA dataset, we identified 120 and 204 differentially expressed genes, respectively. In both the T1D and T2D models, pathway analyses revealed that the top pathways were associated with GA integrity, organization, and trafficking. Quantitative RT-PCR was used to validate a common signature of GA stress that included ATF3, ARF4, CREB3, and COG6. Taken together, these data indicate that GA-associated genes are dysregulated in diabetes and identify putative markers of β-cell GA stress.

Funding

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants R01 DK093954 and UC4 DK104166 (to C.E.-M.), U.S. Department of Veterans Affairs Merit Award I01BX001733 (to C.E.-M.), JDRF 2-SRA-2018-493-A-B (to C.E.-M.), and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, and the George and Frances Ball Foundation (to C.E.-M.). R.N.B. was supported by a NIH NIAID Training Grant (T32 AI060519) and by a JDRF Postdoctoral Fellowship (3-PDF-2017-385-A-N). F.S. was supported by a JDRF postdoctoral fellowship (3-PDF-2016-199-A-N). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors acknowledge the support of the Indiana Diabetes Research Center Islet & Physiology Core (P30 DK097512).

History

Exports

Logo branding

Exports