Identification and Characterization of Hypoxia-Regulated Endothelial Circular RNA

Boeckel, Jes Niels; Jaé, Nicolas; Heumüller, Andreas W.; Chen, Wei; Boon, Reinier A.; Stellos, Konstantinos; Zeiher, Andreas M.; John, David; Uchida, Shizuka; Dimmeler, Stefanie

doi:10.1161/circresaha.115.306319

Cited by 312 publications

(267 citation statements)

References 19 publications

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“…Additional avenues for future investigation could include querying the cardiac Ago2 HITS-CLIP data for other biologically-relevant miR binding sites within coding regions, particularly those which may elicit splice-isoform specific gene suppression. This data resource may also guide future interrogations of intriguing Ago2 bindings sites within intronic regions, long non-coding RNAs (lncRNAs) and perhaps even circular RNAs (circRNAs) (46), as the functional relevance of these sites remains largely unknown. Although our luciferase data mostly point to gene suppression mechanisms for the tested miR binding sites, these experiments need to be followed-up in more biologically-relevant contexts, keeping in mind that some interactions may function as miR ‘sponges’ in competing endogenous RNA (ceRNA) expression networks (47).…”

Section: Discussionmentioning

confidence: 99%

Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

Spengler¹,

Zhang²,

Cheng³

et al. 2016

Nucleic Acids Res

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MicroRNAs (miRs) have emerged as key biological effectors in human health and disease. These small noncoding RNAs are incorporated into Argonaute (Ago) proteins, where they direct post-transcriptional gene silencing via base-pairing with target transcripts. Although miRs have become intriguing biological entities and attractive therapeutic targets, the translational impacts of miR research remain limited by a paucity of empirical miR targeting data, particularly in human primary tissues. Here, to improve our understanding of the diverse roles miRs play in cardiovascular function and disease, we applied high-throughput methods to globally profile miR:target interactions in human heart tissues. We deciphered Ago2:RNA interactions using crosslinking immunoprecipitation coupled with high-throughput sequencing (HITS-CLIP) to generate the first transcriptome-wide map of miR targeting events in human myocardium, detecting 4000 cardiac Ago2 binding sites across >2200 target transcripts. Our initial exploration of this interactome revealed an abundance of miR target sites in gene coding regions, including several sites pointing to new miR-29 functions in regulating cardiomyocyte calcium, growth and metabolism. Also, we uncovered several clinically-relevant interactions involving common genetic variants that alter miR targeting events in cardiomyopathy-associated genes. Overall, these data provide a critical resource for bolstering translational miR research in heart, and likely beyond.

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Section: Discussionmentioning

confidence: 99%

Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

Spengler¹,

Zhang²,

Cheng³

et al. 2016

Nucleic Acids Res

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“…Intriguingly, a recent study in endothelial cells showed that circRNAs are regulated in response to hypoxia and have a biological function as proven by in vitro experiments [11]. Nonetheless, no rigorous reports have been published on circRNAs in murine or human heart cell types.…”

Section: Introductionmentioning

confidence: 99%

Profiling and Validation of the Circular RNA Repertoire in Adult Murine Hearts

Jakobi

Czaja-Hasse²,

Reinhardt³

et al. 2016

Genomics, Proteomics &Amp; Bioinformatics

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For several decades, cardiovascular disease has been the leading cause of death throughout all countries. There is a strong genetic component to many disease subtypes (e.g., cardiomyopathy) and we are just beginning to understand the relevant genetic factors. Several studies have related RNA splicing to cardiovascular disease and circular RNAs (circRNAs) are an emerging player. circRNAs, which originate through back-splicing events from primary transcripts, are resistant to exonucleases and typically not polyadenylated. Initial functional studies show clear phenotypic outcomes for selected circRNAs. We provide, for the first time, a comprehensive catalogue of RNase R-resistant circRNA species for the adult murine heart. This work combines state-of-the-art circle sequencing with our novel DCC software to explore the circRNA landscape of heart tissue. Overall, we identified 575 circRNA species that pass a beta-binomial test for enrichment (false discovery rate of 1%) in the exonuclease-treated sequencing sample. Several circRNAs can be directly attributed to host genes that have been previously described as associated with cardiovascular disease. Further studies of these candidate circRNAs may reveal disease-relevant properties or functions of specific circRNAs.

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“…However, as of today, only one study has been published on the role of circRNAs in vascular cells, with particular attention to regulation by hypoxia in ECs (84). This calls for a more detailed analysis of their role in vascular development and disease.…”

Section: Long-non-coding Rnasmentioning

confidence: 99%

Epigenetics and Vascular Diseases: Influence of Non-coding RNAs and Their Clinical Implications

Elia

2017

Front. Cardiovasc. Med.

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Epigenetics refers to heritable mechanisms able to modulate gene expression that do not involve alteration of the genomic DNA sequence. Classically, mechanisms such as DNA methylation and histone modifications were part of this classification. Today, this field of study has been expanded and includes also the large class of non-coding RNAs (ncRNAs). Indeed, with the extraordinary possibilities introduced by the next-generation sequencing approaches, our knowledge of the mammalian transcriptome has greatly improved. Today, we have identifying thousands of ncRNAs, and unsurprisingly, a direct association between ncRNA dysregulation and development of cardiovascular pathologies has been identified. This class of gene modulators is further divided into short-ncRNAs and long-non-coding RNAs (lncRNAs). Among the short-ncRNA sub-group, the best-characterized players are represented by highly conserved RNAs named microRNAs (miRNAs). miRNAs principally inhibit gene expression, and their involvement in cardiovascular diseases has been largely studied. On the other hand, due to the different roles played by lncRNAs, their involvement in cardiovascular pathology development is still limited, and further studies are needed. For instance, in order to define their roles in the cellular processes associated with the development of diseases, we need to better characterize the details of their mechanisms of action; only then might we be able to develop innovative therapeutic strategies. In this review, we would like to give an overview of the current knowledge on the function of ncRNAs and their involvement in the development of vascular diseases.

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Identification and Characterization of Hypoxia-Regulated Endothelial Circular RNA

Cited by 312 publications

References 19 publications

Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

Profiling and Validation of the Circular RNA Repertoire in Adult Murine Hearts

Epigenetics and Vascular Diseases: Influence of Non-coding RNAs and Their Clinical Implications

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