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Article

Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice

1
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), 14558 Potsdam, Germany
2
German Center for Diabetes Research (DZD), 85764 Munich, Germany
3
Omiqa Bioinformatics, 14195 Berlin, Germany
4
Institute of Nutritional Sciences, University of Potsdam, 14558 Nuthetal, Germany
5
Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, The Brandenburg Medical School Theodor Fontane and The University of Potsdam, 14469 Potsdam, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Csaba Hetényi and Uko Maran
Int. J. Mol. Sci. 2021, 22(16), 8597; https://doi.org/10.3390/ijms22168597
Received: 15 June 2021 / Revised: 28 July 2021 / Accepted: 5 August 2021 / Published: 10 August 2021
Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk. View Full-Text
Keywords: alternative splicing; epigenetic; MicroRNA; RNAseq; diabetes; β-cell failure alternative splicing; epigenetic; MicroRNA; RNAseq; diabetes; β-cell failure
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MDPI and ACS Style

Wilhelmi, I.; Neumann, A.; Jähnert, M.; Ouni, M.; Schürmann, A. Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice. Int. J. Mol. Sci. 2021, 22, 8597. https://doi.org/10.3390/ijms22168597

AMA Style

Wilhelmi I, Neumann A, Jähnert M, Ouni M, Schürmann A. Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice. International Journal of Molecular Sciences. 2021; 22(16):8597. https://doi.org/10.3390/ijms22168597

Chicago/Turabian Style

Wilhelmi, Ilka, Alexander Neumann, Markus Jähnert, Meriem Ouni, and Annette Schürmann. 2021. "Enriched Alternative Splicing in Islets of Diabetes-Susceptible Mice" International Journal of Molecular Sciences 22, no. 16: 8597. https://doi.org/10.3390/ijms22168597

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