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

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.

Genome-Wide Identification and Characterization of CPR5 Genes in Gossypium Reveals Their Potential Role in Trichome Development

“…Unlike the traditional method of only reserving the longest transcript sequence for each gene identified through blastP, in this study, we chose the differential splicing CPR5 sequences for the following analysis. The differential splicing alterations had been proved to produce numerous protein structures and function variances from one gene ( Reddy, 2007 ; Park et al, 2013 ; Rehman et al, 2021 ). In the current study, we had identified multiple protein isoforms from one or two CPR5 genes in some Gossypium species, GhirCPR5.2/GhirCPR5.3,GbarCPR5.1/GbarCPR5.2/GbarCPR5.3, GmusCPR5.2/GmusCPR5.3, GdarCPR5.2/GdarCPR5.3, GlonCPR5.1/GlonCPR5.2 .…”

Inhibition of proline-rich-tyrosine kinase 2 restores cardioprotection by remote ischemic preconditioning in type 2 diabetes mellitus

“…Endothelial function and remote cardioprotection to influence IS after I/R was evaluated in NZO and Bl6 mice, in addition to cardiovascular characterization. As a polygenic mouse model, NZO mice are an established and well-known model resembling characteristic features of T2DM disease in humans: obesity, insulin resistance, severe hyperglycemia and disturbed glucose tolerance [17][18][19][20] . As the prevalence of these conditions is about 60 %, each mouse was tested for manifest T2DM before the further examination.…”

Regulation of endocrine cell alternative splicing revealed by single-cell RNA sequencing in type 2 diabetes pathogenesis

“…Aberrantly spliced genes were identified to associate with diabetes 11 – 13 . It has been reported that the shorter human insulin receptor isoform can prevent downstream insulin signaling, which impairs β-cell survival 14 .…”