Natural RNA circles function as efficient microRNA sponges

• Published in: Nature (London) Vol. 495; no. 7441; pp. 384 - 388
• Main Authors: Hansen, Thomas B., Jensen, Trine I., Clausen, Bettina H., Bramsen, Jesper B., Finsen, Bente, Damgaard, Christian K., Kjems, Jørgen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.03.2013; Nature Publishing Group
• Subjects: 631/337/384/2568; Animals; Argonaute Proteins - metabolism; Biosynthesis; Brain - metabolism; Gene expression; Gene Expression Regulation; Genetic aspects; Genetic regulation; Health aspects; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; letter; Male; Messenger RNA; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; multidisciplinary; Proteins; RNA - genetics; RNA - metabolism; Science; Sex-Determining Region Y Protein - genetics; Sex-Determining Region Y Protein - metabolism; Studies; Denmark
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11993

A natural circular RNA termed ciRS-7 is shown to function as a negative regulator of microRNA; ciRS-7 acts as an efficient sponge for the microRNA miR-7, and is resistant to the usual microRNA-mediated degradation pathway of exonucleolytic RNA decay. How circRNAs round-up miRNAs Circular RNAs (circRNAs) have been detected in animal cells, but their function has been unclear. Two papers, from the laboratories of Nikolaus Rajewsky and Jørgen Kjems, have now defined a function for one circRNA that binds the microRNA miR-7. They find that this circRNA is replete with microRNA binding sites and can act as a 'sponge' capable of binding scores of miRNAs per circRNA molecule. These studies suggest a role for circRNAs in post-transcriptional regulation. 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 1 . 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 2 , 3 , 4 , 5 , 6 , 7 . We previously identified a highly expressed circular RNA (circRNA) in human and mouse brain 8 . 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 ) 9 , 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.