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Updated: Feb 27, 2026
In Silico Identification and Characterization of circRNAs During Host-Pathogen Interactions
Published on: October 21, 2022
Identification of circular RNAs with host gene-independent expression in human model systems for cardiac
D Siede1, K Rapti2, A A Gorska2
1Department Molecular Cardiology and Epigenetics, University of Heidelberg, Heidelberg D-69120, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Mannheim 69120, Heidelberg, Germany.
Insights
Circular RNAs (circRNAs) show dynamic expression in heart cells during development and disease. This study identifies novel circRNAs in human cells and patient samples, suggesting they could be future therapeutic targets for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Epigenetics
Background:
- Cardiovascular disease is a leading cause of mortality, associated with altered RNA splicing and expression.
- Circular RNAs (circRNAs) are formed by back-splicing and have emerged as key regulators of gene expression.
- Understanding circRNA dynamics in cardiac development and disease is crucial for identifying novel biomarkers and therapeutics.
Purpose of the Study:
- To identify and characterize circRNAs in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) during cardiac development and response to stress.
- To investigate the expression dynamics of circRNAs and their host genes in hiPSC-CMs and human dilated cardiomyopathy (DCM) patient samples.
- To explore potential molecular interactions of selected circRNAs with protein complexes.
Main Methods:
- Deep RNA sequencing of hiPSC-CMs to identify circRNAs and analyze their expression.
- Quantitative reverse transcription PCR (qRT-PCR) to validate circRNA expression dynamics.
- RIP-seq experiments in rodent models to investigate circRNA-protein interactions.
Main Results:
- Over 4518 circRNAs were identified in hiPSC-CMs, with 320 showing significant dynamic expression changes.
- 82 circRNAs exhibited expression patterns independent of their host genes.
- Similar circRNA dynamics were observed in human DCM patient samples, and several circRNAs interacted with the ribosome or Argonaute2 complexes.
Conclusions:
- CircRNAs are dynamically expressed in hiPSC-CMs, reflecting cardiac development and stress responses.
- A subset of circRNAs displays host-gene independent regulation and altered expression in DCM patients.
- These findings highlight a novel signature of disease-relevant circRNAs with potential as therapeutic targets for cardiovascular conditions.
Aims:
Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments.
Methods And Results:
Deep RNA sequencing of cardiomyocyte development and β-adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes.
Conclusion:
CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets.
