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Published on: May 19, 2017
Deep Characterization of Circular RNAs from Human Cardiovascular Cell Models and Cardiac Tissue
Tobias Jakobi1,2,3, Dominik Siede4, Jessica Eschenbach1,2
1Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Insights
Circular RNAs (circRNAs) play a role in cardiovascular disease (CVD). This study analyzes cardiac circRNA interactions, modifications, and sequences, revealing novel insights into their function in heart conditions.
Area of Science:
- Molecular Biology
- Genomics
- Cardiovascular Research
Background:
- Cardiovascular disease (CVD) remains a leading cause of mortality globally.
- Circular RNAs (circRNAs) are increasingly implicated in CVD pathogenesis.
- Understanding cardiac circRNA characteristics is crucial for disease insights.
Purpose of the Study:
- To conduct an in-depth analysis of cardiac circRNA sequence, structure, modification, and interactions.
- To identify conserved and model-specific circRNA signatures in cardiac tissues.
- To explore potential functions and regulatory roles of circRNAs in cardiovascular health and disease.
Main Methods:
- Profiling of circRNAs in human induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), healthy and diseased human cardiac tissues, and human umbilical vein endothelial cells (HUVECs).
- Comparative analysis of circRNA sequences, including deviations from genomic sequences.
- Integration of multi-omics data to identify modifications like m6A-methylation and potential Argonaute 2 binding sites.
Main Results:
- Identification of shared and model-specific circRNA expression profiles across different cardiac and endothelial cell models.
- Discovery of 63 positionally conserved circRNAs in human, pig, and mouse hearts.
- Evidence for m6A-methylation in circRNAs, including a novel subclass of AUG circRNAs, and potential association with the RISC complex.
Conclusions:
- Cardiac circRNAs exhibit conserved and specific expression patterns relevant to cardiovascular conditions.
- CircRNA sequence variations and modifications like m6A-methylation are important factors for their function.
- The identification of AUG circRNAs and their enrichment for m6A-methylation opens new avenues for understanding circRNA roles in cardiac biology.
Abstract:
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.
