Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
Tobias Jakobi,
Dominik Siede,
Jessica Eschenbach,
Andreas W. Heumüller,
Martin Busch,
Rouven Nietsch,
Benjamin Meder,
Patrick Most,
Stefanie Dimmeler,
Johannes Backs,
Hugo A. Katus,
Christoph Dieterich
Affiliations
Tobias Jakobi
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Dominik Siede
Institute of Experimental Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Jessica Eschenbach
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany
Andreas W. Heumüller
Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany
Martin Busch
Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), University Hospital Heidelberg, 69120 Heidelberg, Germany
Rouven Nietsch
Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), University Hospital Heidelberg, 69120 Heidelberg, Germany
Benjamin Meder
Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), University Hospital Heidelberg, 69120 Heidelberg, Germany
Patrick Most
Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), University Hospital Heidelberg, 69120 Heidelberg, Germany
Stefanie Dimmeler
Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany
Johannes Backs
German Centre for Cardiovascular Research (DZHK)-Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
Hugo A. Katus
Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), University Hospital Heidelberg, 69120 Heidelberg, Germany
Christoph Dieterich
Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany
For decades, cardiovascular disease (CVD) has been the leading cause of death throughout most developed countries. Several studies relate RNA splicing, and more recently also circular RNAs (circRNAs), to CVD. CircRNAs originate from linear transcripts and have been shown to exhibit tissue-specific expression profiles. Here, we present an in-depth analysis of sequence, structure, modification, and cardiac circRNA interactions. We used human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), human healthy and diseased (ischemic cardiomyopathy, dilated cardiomyopathy) cardiac tissue, and human umbilical vein endothelial cells (HUVECs) to profile circRNAs. We identified shared circRNAs across all samples, as well as model-specific circRNA signatures. Based on these circRNAs, we identified 63 positionally conserved and expressed circRNAs in human, pig, and mouse hearts. Furthermore, we found that the sequence of circRNAs can deviate from the sequence derived from the genome sequence, an important factor in assessing potential functions. Integration of additional data yielded evidence for m6A-methylation of circRNAs, potentially linked to translation, as well as, circRNAs overlapping with potential Argonaute 2 binding sites, indicating potential association with the RISC complex. Moreover, we describe, for the first time in cardiac model systems, a sub class of circRNAs containing the start codon of their primary transcript (AUG circRNAs) and observe an enrichment for m6A-methylation for AUG circRNAs.