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Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

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posted on 25.05.2021, 17:01 by Helmut Hiller, Dawn E. Beachy, Joseph J. Lebowitz, Stefanie Engler, Justin R. Mason, Douglas R. Miller, Irina Kusmarteva, Laura M. Jacobsen, Amanda L. Posgai, Habibeh Khoshbouei, Richard A. Oram, Desmond A. Schatz, Andrew T. Hattersley, Bernd Bodenmiller, Mark A. Atkinson, Harry S. Nick, Clive H. Wasserfall
Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a “monogenetic transcriptomic strategy,” we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized in situ using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2a-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder’s pathogenesis.

Funding

This work was supported by the Network for Pancreatic Organ donors with Diabetes (nPOD; RRID-SCR_014541), a collaborative type 1 diabetes research project sponsored by JDRF (nPOD:5-SRA-2018-557-Q-R) and The Leona M. and Harry B. Helmsley Charitable Trust (Grant# 2018PG-type 1 diabetes053). This research was also supported by the National Institutes of Health (DK108132 AI42288, and S10OD020026).

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