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  Alternative exon splicing and differential expression in pancreatic islets reveals candidate genes and pathways implicated in early diabetes development

Rehman, S. U., Schallschmidt, T., Rasche, A., Knebel, B., Stermann, T., Altenhofen, D., et al. (2021). Alternative exon splicing and differential expression in pancreatic islets reveals candidate genes and pathways implicated in early diabetes development. Mammalian Genome, 32(3), 153-172. doi: 10.1007/s00335-021-09869-1.

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Rehman, Sayeed Ur , Author
Schallschmidt, Tanja , Author
Rasche, Axel1, Author              
Knebel, Birgit, Author
Stermann, Torben, Author
Altenhofen, Delsi , Author
Herwig, Ralf1, Author              
Schürmann, Annette , Author
Chadt, Alexandra , Author
Al‑Hasani, Hadi, Author
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1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              

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 Abstract: Type 2 diabetes (T2D) has a strong genetic component. Most of the gene variants driving the pathogenesis of T2D seem to target pancreatic β-cell function. To identify novel gene variants acting at early stage of the disease, we analyzed whole transcriptome data to identify differential expression (DE) and alternative exon splicing (AS) transcripts in pancreatic islets collected from two metabolically diverse mouse strains at 6 weeks of age after three weeks of high-fat-diet intervention. Our analysis revealed 1218 DE and 436 AS genes in islets from NZO/Hl vs C3HeB/FeJ. Whereas some of the revealed genes present well-established markers for β-cell failure, such as Cd36 or Aldh1a3, we identified numerous DE/AS genes that have not been described in context with β-cell function before. The gene Lgals2, previously associated with human T2D development, was DE as well as AS and localizes in a quantitative trait locus (QTL) for blood glucose on Chr.15 that we reported recently in our N2(NZOxC3H) population. In addition, pathway enrichment analysis of DE and AS genes showed an overlap of only half of the revealed pathways, indicating that DE and AS in large parts influence different pathways in T2D development. PPARG and adipogenesis pathways, two well-established metabolic pathways, were overrepresented for both DE and AS genes, probably as an adaptive mechanism to cope for increased cellular stress. Our results provide guidance for the identification of novel T2D candidate genes and demonstrate the presence of numerous AS transcripts possibly involved in islet function and maintenance of glucose homeostasis.

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Language(s): eng - English
 Dates: 2021-04-032021-04-202021-06
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1007/s00335-021-09869-1
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Title: Mammalian Genome
Source Genre: Journal
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Publ. Info: New York : Springer-Verlag
Pages: 20 Volume / Issue: 32 (3) Sequence Number: - Start / End Page: 153 - 172 Identifier: ISSN: 0938-8990
CoNE: https://pure.mpg.de/cone/journals/resource/954925571879