title: circRNA biogenesis competes with pre-mRNA splicing.
abstract: Circular RNAs (circRNAs) are widely expressed noncoding RNAs. However, their biogenesis and possible functions are poorly understood. Here, by studying circRNAs that we identified in neuronal tissues, we provide evidence that animal circRNAs are generated cotranscriptionally and that their production rate is mainly determined by intronic sequences. We demonstrate that circularization and splicing compete against each other. These mechanisms are tissue specific and conserved in animals. Interestingly, we observed that the second exon of the splicing factor muscleblind (MBL/MBNL1) is circularized in flies and humans. This circRNA (circMbl) and its flanking introns contain conserved muscleblind binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL binding sites. Together, our data suggest that circRNAs can function in gene regulation by competing with linear splicing. Furthermore, we identified muscleblind as a factor involved in circRNA biogenesis.
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Reut
authors.initials: R
authors.lastname: Ashwal-Fluss
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Nagarjuna Reddy
authors.initials: NR
authors.lastname: Pamudurti
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Andranik
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Osnat
authors.initials: O
authors.lastname: Bartok
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Mor
authors.initials: M
authors.lastname: Hanan
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
authors.forename: Naveh
authors.initials: N
authors.lastname: Evantal
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin 13092, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Memczak
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Berlin 13092, Germany. Electronic address: rajewsky@mdc-berlin.de.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Biological Chemistry Department, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address: skadener@mail.huji.ac.il.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kadener
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D012313:RNA / Q000096:biosynthesis*; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing; D000079962:RNA, Circular; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D029721:Drosophila Proteins; D009687:Nuclear Proteins; D012322:RNA Precursors; D000079962:RNA, Circular; D012333:RNA, Messenger; C109271:mbl protein, Drosophila; D012313:RNA