title: Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.
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.
authors.affiliation: 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.
authors.forename: Andranik
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: 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.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Memczak
authors.affiliation: 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.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Wyler
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Torti
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Hagit T
authors.initials: HT
authors.lastname: Porath
authors.affiliation: 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.
authors.forename: Marta R
authors.initials: MR
authors.lastname: Orejuela
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Joseph Stelzmann Straße 9B, 50931 Köln, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Piechotta
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Erez Y
authors.initials: EY
authors.lastname: Levanon
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Landthaler
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Joseph Stelzmann Straße 9B, 50931 Köln, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dieterich
authors.affiliation: 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.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D012313:RNA / Q000737:chemistry / Q000378:metabolism*; D017393:RNA Editing; D034622:RNA Interference; D000079962:RNA, Circular; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029742:Caenorhabditis elegans Proteins; D000079962:RNA, Circular; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012313:RNA; C000595356:ADAR protein, human; D000243:Adenosine Deaminase