Luminal breast cancer-specific circular RNAs uncovered by a novel tool for data analysis
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Lucia Coscujuela Tarrero1,2, Giulio Ferrero1,2,3, Valentina Miano1,2, Carlo De Intinis2, Laura Ricci1,2, Maddalena Arigoni4, Federica Riccardo4, Laura Annaratone5, Isabella Castellano5, Raffaele A. Calogero1,4, Marco Beccuti3, Francesca Cordero1,3 and Michele De Bortoli1,2
1Center for Molecular Systems Biology, University of Turin, Turin, Italy
2Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
3Department of Computer Science, University of Turin, Turin, Italy
4Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
5Department of Medical Sciences, University of Turin, Turin, Italy
Michele De Bortoli, email: [email protected]
Keywords: circRNA; breast cancer; biomarker; alternative splicing; estrogen receptor
Received: July 28, 2017 Accepted: February 12, 2018 Epub: February 19, 2018 Published: March 06, 2018
Circular RNAs are highly stable molecules present in all eukaryotes generated by distinct transcript processing. We have exploited poly(A-) RNA-Seq data generated in our lab in MCF-7 breast cancer cells to define a compilation of exonic circRNAs more comprehensive than previously existing lists. Development of a novel computational tool, named CircHunter, allowed us to more accurately characterize circRNAs and to quantitatively evaluate their expression in publicly available RNA-Seq data from breast cancer cell lines and tumor tissues. We observed and confirmed, by ChIP analysis, that exons involved in circularization events display significantly higher levels of the histone post-transcriptional modification H3K36me3 than non-circularizing exons. This result has potential impact on circRNA biogenesis since H3K36me3 has been involved in alternative splicing mechanisms. By analyzing an Ago-HITS-CLIP dataset we also found that circularizing exons overlapped with an unexpectedly higher number of Ago binding sites than non-circularizing exons. Finally, we observed that a subset of MCF-7 circRNAs are specific to tumor versus normal tissue, while others can distinguish Luminal from other tumor subtypes, thus suggesting that circRNAs can be exploited as novel biomarkers and drug targets for breast cancer.
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