Circular RNAs are a large class of animal RNAs with regulatory potency

Abstract

Circular RNAs (circRNAs) in animals are an enigmatic class of RNA with unknown function. To explore circRNAs systematically, we sequenced and computationally analysed human, mouse and nematode RNA. We detected thousands of well-expressed, stable circRNAs, often showing tissue/developmental-stage-specific expression. Sequence analysis indicated important regulatory functions for circRNAs. We found that a human circRNA, antisense to the cerebellar degeneration-related protein 1 transcript (CDR1as), is densely bound by microRNA (miRNA) effector complexes and harbours 63 conserved binding sites for the ancient miRNA miR-7. Further analyses indicated that CDR1as functions to bind miR-7 in neuronal tissues. Human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7, suggesting that CDR1as is a miRNA antagonist with a miRNA-binding capacity ten times higher than any other known transcript. Together, our data provide evidence that circRNAs form a large class of post-transcriptional regulators. Numerous circRNAs form by head-to-tail splicing of exons, suggesting previously unrecognized regulatory potential of coding sequences.

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

“…Distinct from miRNA, circRNA was impregnable to RNA exonuclease, as its special circular‐closure structure made itself more stable than linear RNA 31, 32, 33, 34, 35. 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.…”

“…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

“…Also, circRNA often show tissue/developmental stage‐specific expression 28. These characteristics give circRNAs the potential of being ideal biomarkers for various diseases.…”

Does the linear Sry transcript function as a ceRNA for miR-138? The sense of antisense

“…In both reports, the authors demonstrated that a ~1.5-kb single-stranded antisense circRNA molecule (human CDR1as or ciRS-7 ) containing multiple miR-7 binding sites densely arranged, acts as a natural miRNA sponge, by capturing complexes formed by miR-7/Ago2. Memczak et al observed that human CDR1as expression in zebrafish impaired midbrain development, similar to knocking down miR-7 5 .…”

“…Recently, Hansen et al and Memczak et al described a new class of post-transcriptional regulatory RNAs that behave as circular endogenous RNA sponges (circRNAs) in two back-to-back papers published in Nature 5, 6 . In both reports, the authors demonstrated that a ~1.5-kb single-stranded antisense circRNA molecule (human CDR1as or ciRS-7 ) containing multiple miR-7 binding sites densely arranged, acts as a natural miRNA sponge, by capturing complexes formed by miR-7/Ago2.…”