Natural RNA circles function as efficient microRNA sponges

Abstract

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression that act by direct base pairing to target sites within untranslated regions of messenger RNAs. Recently, miRNA activity has been shown to be affected by the presence of miRNA sponge transcripts, the so-called competing endogenous RNA in humans and target mimicry in plants. We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain. Here we show that this circRNA acts as a miR-7 sponge; we term this circular transcript ciRS-7 (circular RNA sponge for miR-7). ciRS-7 contains more than 70 selectively conserved miRNA target sites, and it is highly and widely associated with Argonaute (AGO) proteins in a miR-7-dependent manner. Although the circRNA is completely resistant to miRNA-mediated target destabilization, it strongly suppresses miR-7 activity, resulting in increased levels of miR-7 targets. In the mouse brain, we observe overlapping co-expression of ciRS-7 and miR-7, particularly in neocortical and hippocampal neurons, suggesting a high degree of endogenous interaction. We further show that the testis-specific circRNA, sex-determining region Y (Sry), serves as a miR-138 sponge, suggesting that miRNA sponge effects achieved by circRNA formation are a general phenomenon. This study serves as the first, to our knowledge, functional analysis of a naturally expressed circRNA.

CiRS‐7 targeting miR‐7 modulates the progression of non‐small cell lung cancer in a manner dependent on NF‐κB signalling

“…Hence, circRNAs were more likely to be implicated within the mechanisms that gave rise to dysfunctional bioactivities, such as the onset and aggravation of cancers. For instance, ciRS‐7, the natural antisense transcript of cerebellar degeneration‐associated protein 1 (CRD1), contained approximately 70 MREs of miR‐7 24, 32, 36. Its high expression within cytoplasms could effectively lower miR‐7 activity through binding to it, thereby down‐regulating the expressions of insulin‐like growth factor‐1 receptor (IGF1R), epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) 37, 38, 39…”

Identification of circular RNAs hsa_circ_0044235 in peripheral blood as novel biomarkers for rheumatoid arthritis

“…It was reported that circRNAs could function as miRNA ‘sponges’, and thus naturally sequester or competitively suppress the activity of target miRNA 35. To investigate the function of hsa_circ_0044235, the potential miRNA targets of hsa_circ_0044235 were predicted by using Arraystar's miRNA target prediction software.…”

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

“…A circRNA sponge for miR‐7 (ciRS‐7) has been of particular interest after Hansen et al. 129 found that ciRS‐7 and miR‐7 were coexpressed in the mouse brain. ciRS‐7 contains more than 70 conserved miRNA target sites and strongly suppresses miR‐7 activity, resulting in increased levels of miR‐7 targets.…”