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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 2021-05-25, 17:01 authored 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. WasserfallType
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.