Titin Forms Circles
Regulation by Heart Failure and the RNA-Binding Protein RBM20
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Although 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.
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In this issue of Circulation Research, Khan et al7 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 al5 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 …