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A combined computational pipeline to detect circular RNAs in human cancer cells under hypoxic stress
Antonella Di Liddo 1,2, Camila de Oliveira Freitas Machado 2,3, Sandra Fischer4, Stefanie Ebersberger5, Andreas W. Heumüller3, Julia E. Weigand4, Michaela Müller-McNicoll2, and Kathi Zarnack 1,*
1 Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany
2 Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt am Main, Germany
3 Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt am Main, Germany
4 Department of Biology, Technical University Darmstadt, Germany
5 Institute of Molecular Biology (IMB), Mainz, Germany
*Correspondence to:Kathi Zarnack, E-mail:
J Mol Cell Biol, Volume 11, Issue 10, October 2019, 829-844,
Keyword: circular RNA, computational pipeline, differential expression, cancer cells, hypoxia, RNA-Seq
Hypoxia is associated with several diseases, including cancer. Cells that are deprived of adequate oxygen supply trigger transcriptional and post-transcriptional responses, which control cellular pathways such as angiogenesis, proliferation, and metabolic adaptation. Circular RNAs (circRNAs) are a novel class of mainly non-coding RNAs, which have been implicated in multiple cancers and attract increasing attention as potential biomarkers. Here, we characterize the circRNA signatures of three different cancer cell lines from cervical (HeLa), breast (MCF-7), and lung (A549) cancer under hypoxia. In order to reliably detect circRNAs, we integrate available tools with custom approaches for quantification and statistical analysis. Using this consolidated computational pipeline, we identify ~12000 circRNAs in the three cancer cell lines. Their molecular characteristics point to an involvement of complementary RNA sequences as well as trans-acting factors in circRNA biogenesis, such as the RNA-binding protein HNRNPC. Notably, we detect a number of circRNAs that are more abundant than their linear counterparts. In addition, 64 circRNAs significantly change in abundance upon hypoxia, in most cases in a cell type-specific manner. In summary, we present a comparative circRNA profiling in human cancer cell lines, which promises novel insights into the biogenesis and function of circRNAs under hypoxic stress.