Hansen, Thomas B6; Jensen, Trine I7; Clausen, Bettina H8; Bramsen, Jesper Bertram4; Finsen, Bente8; Damgaard, Christian Kroun5; Kjems, Jørgen5
1 Finsen-gruppen, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU2 Laboratoriet for Naturlige Interaktive Systemer, Faculty of Science, SDU3 Health Promotion and Prevention, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU4 Institut for Klinisk Medicin - Molekylær medicinsk afdeling (MOMA)5 Institut for Molekylærbiologi og Genetik6 Laboratoriet for Naturlige Interaktive Systemer, Faculty of Science, SDU7 Health Promotion and Prevention, National Institute of Public Health, Det Sundhedsvidenskabelige Fakultet, SDU8 Finsen-gruppen, Department of Molecular Medicine, Det Sundhedsvidenskabelige Fakultet, SDU
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.
Nature, 2013, Vol 495, Issue 7441, p. 384-8
Animals; Argonaute Proteins; Brain; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Male; Mice; Mice, Inbred C57BL; MicroRNAs; RNA; Sex-Determining Region Y Protein