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Cell Rep. 2015 Jan 13;10(2):170-7. doi: 10.1016/j.celrep.2014.12.019. Epub 2014 Dec 31.

Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.

Author information

1
Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Robert Roessle Straße 10, 13125 Berlin-Buch, Germany.
2
Laboratory for RNA Biology and Posttranscriptional Regulation, Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Robert Roessle Straße 10, 13125 Berlin-Buch, Germany.
3
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
4
Max Planck Institute for Biology of Ageing, Cologne, Joseph Stelzmann Straße 9B, 50931 Köln, Germany.
5
Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Robert Roessle Straße 10, 13125 Berlin-Buch, Germany. Electronic address: rajewsky@mdc-berlin.de.

Abstract

Circular RNAs (circRNAs) are a large class of animal RNAs. To investigate possible circRNA functions, it is important to understand circRNA biogenesis. Besides human ALU repeats, sequence features that promote exon circularization are largely unknown. We experimentally identified circRNAs in C. elegans. Reverse complementary sequences between introns bracketing circRNAs were significantly enriched in comparison to linear controls. By scoring the presence of reverse complementary sequences in human introns, we predicted and experimentally validated circRNAs. We show that introns bracketing circRNAs are highly enriched in RNA editing or hyperediting events. Knockdown of the double-strand RNA-editing enzyme ADAR1 significantly and specifically upregulated circRNA expression. Together, our data support a model of animal circRNA biogenesis in which competing RNA-RNA interactions of introns form larger structures that promote circularization of embedded exons, whereas ADAR1 antagonizes circRNA expression by melting stems within these interactions.

PMID:
25558066
DOI:
10.1016/j.celrep.2014.12.019
[Indexed for MEDLINE]
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