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

By Andranik Ivanov, Sebastian Memczak, E. Wyler, F. Torti, Hagit T. Porath, M. R. Orejuela, Michael Piechotta, E. Levanon, Markus Landthaler, Christoph Dieterich and 1 more. Cell Reports, 2015

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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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9ba07dacb28a24b22c26943be1b825794c827944

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Citations in the corpus

The bioinformatics toolbox for circRNA discovery and analysis (2020, background): “These molecules have been identified in many species including humans [8], mouse [9], nematode [10], plant [11] and archaea [12].”
Detecting circular RNAs: bioinformatic and experimental challenges (2016, methodology): “‘Hotspot’ genes that produce multiple circRNA isoforms using U2 splice signals were initially identified using a statistical strategy 6 and have also recently been reported 8,9 using find_circ 11 , although only one group 8 has experimentally validated some of these predictions.”
Identification and Characterization of Circular RNAs As a New Class of Putative Biomarkers in Human Blood (2015, methodology): “In this study we used rRNA depleted RNA - seq data from whole blood samples ( own data ) , fetal cerebellum ( ENCODE accession : ENCSR000AEW ) fetal liver ( ENCODE accession : ENCSR000AFB ) and HEK293 [ 30 ] ( S4 Table ) .”
CircNet: a database of circular RNAs derived from transcriptome sequencing data (2015, background): “An integrated genome browser illustrates the position of circRNAs in the human genome, and relative locations of repeat sequences are presented to address the issue of circRNA biogenesis as the biogenesis of circRNAs correlates to repeats in the flanking area (13,32).”
Circular RNAs: analysis, expression and potential functions (2016, methodology): “This hypothesis was tested using short hairpin RNA (shRNA)-mediated knockdown of ADAR and revealed a subset of circRNAs with increased abundance after shRNA treatment, whereas other circRNAs exhibited unchanged levels (Ivanov et al., 2015; Rybak-Wolf et al., 2015).”
CircRNA: functions and properties of a novel potential biomarker for cancer (2017, background): “With technological breakthroughs in high-throughput deep sequencing, large numbers of circRNAs have been recently found in human [11, 20, 40], mouse [11, 20], nematodes [11, 41], zebrafish [42], Drosophila [43], protists [44] and plants [44].”