The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells

Abstract

Among the identified thousands of circular RNAs (circRNA) in humans and animals, Cdr1as (also known as CiRS-7) was recently demonstrated to act as a powerful miR-7 sponge/inhibitor in developing midbrain of zebrafish, suggesting a novel mechanism for regulating microRNA functions. MiR-7 is abundantly expressed in islet cells, but overexpressing miR-7 in transgenic mouse β cells causes diabetes. Therefore, we infer that Cdr1as expression may inhibit miR-7 function in islet cells, which in turn improves insulin secretion. Here, we show the first characterization of Cdr1as expression in islet cells, which was upregulated by long-term forskolin and PMA stimulation, but not high glucose, indicating the involvement of cAMP and PKC pathways. Remarkably, both insulin content and secretion were significantly increased by overexpression of Cdr1as in islet cells. We further identified a new target Myrip in the Cdr1as/miR-7 pathway that regulates insulin granule secretion, and also another target Pax6 that enhances insulin transcription. Taken together, our findings revealed the effects of the strongly interacting pair of Cdr1as/miR-7 on insulin secretion, which may become a new target for improving β cell function in diabetes.

Hsa_circ_0054633 in Peripheral Blood Can be Used as a Diagnostic Biomarker of Pre-Diabetes and Type 2 Diabetes Mellitus

“…Regarding diabetes, cerebellar degeneration-related autoantigen 1 (CDR1) is a protein coding gene located in Xq27.1. As the natural antisense transcripts of CDR1, circRNA-CDR1 has been found to affect insulin secretion and b cell renewal [24]. In this study, we compared the expression profile of circRNAs in the peripheral blood of T2DM patients and matched control subjects by microarray analysis and then confirmed our findings in larger independent cohorts.…”

Embryonic circular RNAs at tandem duplicated genes in zebrafish present new paradigm in gene expression

“…The biogenesis of circRNAs has been shown to be modulated by circularisation "signals" such as complementary sequences and/or secondary structures, which are embedded within the introns that flank circularised exons 7,8,9 . In terms of circRNA function, it has been suggested that they may function as miRNA sponges 10,3,11 , a finding further supported by a recent study of circRNAs in adult zebrafish 12 . CircRNAs can also regulate transcription of their parental genes in the nucleus 13 , and, in certain cases, may be translated into proteins 14 .…”

CircRNA-Cdr1as Exerts Anti-Oncogenic Functions in Bladder Cancer by Sponging MicroRNA-135a

“…A previous study has reported that Cdr1as serves as a molecular sponge of miR-7 and conducts important functions in different biological or pathological progresses, including myocardial infarction [32], hepatocellular carcinoma [23], insulin transcription and secretion [22] and brain development [22]. We detected the expression of miR-7 and miR-135a in 29 pairs of bladder cancer tissues and ANTs.…”

“…Ectopic Cdr1as expression in zebrafish impairs midbrain development, which is similar to knocking down miR-7 [11]. In islet cells, Cdr1as regulates insulin transcription and secretion via miR-7 and its targets [22]. Moreover, it serves as an oncogene in hepatocellular carcinoma through targeting miR-7 expression [23].…”