A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223

Wang, Kun; Long, Bo; Liu, Fang; Jx, Wang; Liu, Cui-Yun; Zhao, Bing; Zhou, Lu; Sun, Tao; Wang, Man; Yu, Tao; Gong, Ying; Liu, Jia; Dong, Yanhan; Li, Na; Li, Peifeng

doi:10.1093/eurheartj/ehv713

Cited by 765 publications

(628 citation statements)

References 47 publications

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“…While circ-Foxo3 promotes cardiac cell death, a circular RNA (HRCR) was found to protect the heart from pathological hypertrophy and heart failure by sequestering and inhibiting miR-223 activity as an endogenous miRNA sponge. 23 In general, circRNAs in the cardiovascular system seem promising as therapeutic targets. Cancer Bachmayr-Heyda and colleagues were the first to report a global reduction of circRNA abundance in colorectal cancer cell lines and cancer tissues compared to normal tissues, and they discovered a negative correlation between global circular RNA abundance and proliferation.…”

Section: Cardiovascular Diseasementioning

confidence: 99%

“…Genome-wide RNA-sequencing analyses have now identified a considerable number of circRNAs derived from backsplicing. Although they are generally expressed at low levels, increasing evidence has shown that circRNAs are linked to physiological development 15 and different diseases, such as neurological dystrophy, 21 cardiovascular diseases, [22][23][24][25] and cancer. [26][27][28] Recently, circRNAs have also been shown to be enriched and stable in plasma, 29 saliva, 30 and even in serum exosomes, 31 indicating the potential of circRNAs as readable biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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Circular RNA from backspliced exons (or exonic circular RNA, circRNA) is a type of covalently closed noncolinear RNA that was recently rediscovered in eukaryotes. Although circRNAs are often expressed at low levels, emerging evidence indicates that many circRNAs are linked to physiological development and various diseases. Notably, circRNAs have been shown to serve as oncogenic stimuli or tumor suppressors in cancer. circRNAs may regulate gene expression through different mechanisms. In addition, circRNAs have been shown to be useful as biomarkers of diseases due to their stability, specific expression and relation to diseases both in cells and in extracellular fluid. This review summarizes current knowledge of human circRNAs and discusses the emerging role and clinical implication of these multifarious transcripts.

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Section: Cardiovascular Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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“…3 In addition, two more bioinformatically oriented studies profiled circRNAs in human, mouse, and rat heart tissue and provided a comprehensive catalog of RNase R-resistant circRNA species. 4,5 Recently, a heart-related circRNA was proposed to control hypertrophy, 6 suggesting that circRNAs may elicit functions in cardiomyocytes as well.…”

Section: Editorialmentioning

confidence: 99%

“…4,5 Recently, a heart-related circRNA was proposed to control hypertrophy, 6 suggesting that circRNAs may elicit functions in cardiomyocytes as well.…”

mentioning

confidence: 99%

Titin Forms Circles

Dimmeler

2016

Circulation Research

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A lthough already discovered in 1976, 1 circular RNAs (circRNAs) remained largely unrecognized in the following decades or were even disregarded as transcriptional artifacts. Recent advances in RNA-sequencing technology and computational approaches, however, lead to the identification of numerous circRNAs in different transcriptomes.2 On the molecular level, circRNAs are generated primarily by a specific form of alternative splicing, so-called back-splicing, catalyzed by the spliceosomal machinery. Generally, little is known about the expression, regulation, and function of circRNAs. In the cardiovascular field, a recent study identified numerous hypoxia-responsive circRNAs in endothelial cells and showed a proangiogenic function for the circular transcript of ZNF292 (zinc finger protein 292).3 In addition, two more bioinformatically oriented studies profiled circRNAs in human, mouse, and rat heart tissue and provided a comprehensive catalog of RNase R-resistant circRNA species. 4,5 Recently, a heart-related circRNA was proposed to control hypertrophy, 6 suggesting that circRNAs may elicit functions in cardiomyocytes as well. Article, see p 996In this issue of Circulation Research, Khan et al 7 performed whole-transcriptome-based circRNA profiling in left ventricle RNA samples, comparing control individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (DCM) patients and identified 826 back-splice junctions common to these 3 sample groups. Strikingly, approximately one tenth of these shared back-splice sites arose from the titin transcript solely. A detailed biochemical survey of 22 selected candidate circRNAs established them as bona fide circRNAs because they were shown to be resistant to RNase R, enriched in poly(A)-negative fractions, and validated on sequence level by Sanger sequencing, a finding that is consistent with the results from Werfel et al 5 who also reported and validated titin circRNAs. Moreover, an RT-PCR-based differential expression analysis uncovered a reduction of circRNA formation from the titin host gene in DCM samples, whereas linear titin transcript levels were not significantly affected. This strongly argues for a specific interference of heart failure with the biogenesis of titin circRNAs, rather than for a secondary reduction of circRNAs by the inhibition of titin transcription. Because DCM is linked to aberrant splicing of titin pre-mRNA, originating from mutations in the splicing factor RNA-binding motif protein 20 (RBM20), 8 the authors investigated whether RBM20 is also essential for titin-derived circRNA biogenesis. In this context, they found RBM20-binding sites to be enriched in the introns flanking the identified titin back-splice junctions. In vivo, RBM20 null mice showed an early onset of DCM, impaired cardiac function, and aberrant titin splicing. To elucidate the role of RBM20 in titin circRNA biogenesis in more detail, Khan et al 7 analyzed the expression of circRNAs that originate from pre-mRNA regions that critically depend on RBM20 processing (Ig and PEVK...

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“…In addition, statistically based splicing detection revealed that tissue-specific RNAs in the heart and lung are markedly induced during human fetal development [3]. Recent studies in this field have revealed that circRNAsare involved in several diseases, such as Alzheimer's disease [4], heart failure [9], Moyamoy disease [10], and cancers [5,6,[11][12][13][14], whereby they function as miRNA sponges. Furthermore, researchers have identified more than 400 circRNAs in human cell-free saliva (CFS) [15] and have detected thousands of circRNAs in human blood from healthy individuals [16], suggesting that circRNAs could exist in some body fluids.…”

Section: Introductionmentioning

confidence: 99%

Application of droplet digital PCR in quantitative detection of the cell-free circulating circRNAs

Chen

Zhang

Tan

et al. 2017

Biotechnology & Biotechnological Equipment

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Diagnostics based on circulating circular RNA (circRNA) is an emerging field for noninvasive molecular diagnosis, owing to the stable circular structure of circRNA. However, the uniquely circular structure still poses a challenge for circRNA quantification in the research community. Here, we verified the discrepancy in the circRNA quantification by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and reverse transcription-droplet digital polymerase chain reaction (RT-ddPCR), which is caused by the rolling reverse transcription (RT) product originating from the circular structure. In addition, we detected the stability of cell-free circRNA in serum/ plasma and determined the pre-analysis sampling procedure that will compromise the quantification of circRNA. Our results showed that prolonged RT incubation time resulted in multiple PCR products from circular RNA, which will reduce the accuracy of circRNA quantification by RT-qPCR technology, whereas ddPCR can address this limitation and could be a good alternative to qPCR for circRNA quantification. CircRNA showed a high stability in promptly separated serum/ plasma but not in delay-separated samples.

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A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223

Abstract: These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Cited by 765 publications

References 47 publications

The emerging role and clinical implication of human exonic circular RNA

The emerging role and clinical implication of human exonic circular RNA

Titin Forms Circles

Application of droplet digital PCR in quantitative detection of the cell-free circulating circRNAs

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