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

Sebastian Memczak, Marvin Jens, Antigoni Elefsinioti, Francesca Torti, Janna Krueger, Agnieszka Rybak, Luisa Maier, Sebastian D. Mackowiak, Lea H. Gregersen, Mathias Munschauer, Alexander Loewer, Ulrike Ziebold, Markus Landthaler, Christine Kocks, Ferdinand le Noble and Nikolaus Rajewsky ()
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Sebastian Memczak: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Marvin Jens: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Antigoni Elefsinioti: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Francesca Torti: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Janna Krueger: Angiogenesis and Cardiovascular Pathology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Agnieszka Rybak: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Luisa Maier: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Sebastian D. Mackowiak: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Lea H. Gregersen: RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Mathias Munschauer: RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Alexander Loewer: Signaling Dynamics in Single Cells, Max-Delbrück-Center for Molecular Medicine
Ulrike Ziebold: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Markus Landthaler: RNA Biology and Post-Transcriptional Regulation, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Christine Kocks: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Ferdinand le Noble: Angiogenesis and Cardiovascular Pathology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany
Nikolaus Rajewsky: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany

Nature, 2013, vol. 495, issue 7441, 333-338

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature11928

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