Our new study was undertaken to help to uncover potential functions of circular RNAs (circRNAs) that are relevant in cardiovascular disease (CVD) in cardiac model systems and organisms. The study defines a strongly conserved core set of circRNAs in human heart tissue, human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), as well as mouse and pig heart. These circRNAs are promising potential targets for further studies because their function is likely conserved and therefore may be important in development and progression of CVD.
We employed a specialized deep sequencing approach to generate comprehensive maps of circRNA exon composition in hiPSC-CMs, human umbilical vein cells (HUVECs), and human hearts, which are required for more confident functional studies.
We identified shared circRNAs across all samples, as well as model-specific circRNA signatures and moreover identified a core set of 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-modification of circRNAs, potentially linked to translation as well as circRNAs overlapping with potential Agonaut2 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-modifications and ribosome association.