Circular RNAs as novel regulators of β-cell functions in normal and disease conditions

Abstract

ObjectiveThere is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of β-cell activities and in diabetes development. Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown. The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of β-cells functions.MethodsWe used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets. We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, β-cell proliferation, and apoptosis.ResultsWe identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets. The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice. Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced β-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7. Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key β-cell genes, such as Slc2a2, Akt1, and Mtpn.ConclusionsOur findings point to circular RNAs as novel regulators of β-cell activities and suggest an involvement of this novel class of non-coding RNAs in β-cell dysfunction under diabetic conditions.

Islet-expressed circular RNAs are associated with type 2 diabetes status in human primary islets and in peripheral blood

“…Cell-type specific circRNA expression has previously been reported in human pancreatic α, β and δ cells [17], but these profiles were not circRNA-specific, being extracted from published NGS data in the absence of RNase R treatment to remove linear RNA. Other human islet circRNA profiles have been generated using microarray approaches, which will capture only known cir-cRNAs [18].…”

Targeting pericyte–endothelial cell crosstalk by circular RNA-cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction

“…Increasing evidence has shown that circRNAs play important roles in cell proliferation, apoptosis, mobility, and differentiation (7,10,11). circRNA dysregulation has been observed in several diseases, such as neurological diseases, cardiovascular diseases, cancers, and diabetes (12)(13)(14)(15). Recently, several studies have highlighted the importance of circular RNAs in vascular EC dysfunction (16)(17)(18)(19).…”

Current status and potential role of circular RNAs in neurological disorders

“…CiRS-7 is a circRNA that is highly abundant and specifically expressed in the mammalian brain (Hansen et al 2011). CiRS-7 contains multiple anti-miR-7 sequences, suggesting that it may function as a sponge to quench/sequester the normal functions of miR-7 in cancer, myocardial infarction, and diabetes (Xu et al 2015;Geng et al 2016;Stoll et al 2018;Li et al 2018b). In addition, ciRS-7 can interact with protein subunits, thus acting as 'scaffolding' for RBP in cancer (Ledford 2013;Jeck and Sharpless 2014).…”