FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4293490614> ?p ?o ?g. }

• W4293490614 endingPage "717" @default.
• W4293490614 startingPage "715" @default.
• W4293490614 abstract "HomeCirculationVol. 146, No. 9Triadin-Antisense: An lncRNA in the Backstage of Cardiac Alternative Splicing Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTriadin-Antisense: An lncRNA in the Backstage of Cardiac Alternative Splicing Pablo Montañés-Agudo, MSc and Yigal M. Pinto, MD, PhD Pablo Montañés-AgudoPablo Montañés-Agudo https://orcid.org/0000-0002-8873-1937 Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Meibergdreef 9, The Netherlands. Search for more papers by this author and Yigal M. PintoYigal M. Pinto Correspondence to: Yigal M. Pinto, MD, PhD, Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. Email E-mail Address: [email protected] Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Meibergdreef 9, The Netherlands. Search for more papers by this author Originally published29 Aug 2022https://doi.org/10.1161/CIRCULATIONAHA.122.061232Circulation. 2022;146:715–717We increasingly recognize that noncoding RNAs provide a vast and multifaceted regulatory landscape in the heart. Herein, long noncoding RNAs (lncRNAs) represent a sizable proportion of larger noncoding RNAs with versatile functions. lncRNAs are quite heterogeneous. As a class, they share the requirement of at least 200 nucleotides, and they do not have apparent protein-coding potential.1 However, some lncRNAs have lately been found to be able to translate into peptides, making their functions even more versatile.2 We still do not know the function of most lncRNAs, but we do know that they are as abundant as coding mRNAs. The last release of the human genome consortium GENCODE (version 40)3 counts 18 805 annotated lncRNA genes versus 19 988 protein-coding genes. Functionally, lncRNAs can regulate important processes within the cell. For instance, they regulate gene expression by directly interacting with transcription factors, by creating discrete compartments within the nucleus or by guiding chromatin modification.4 Alternative splicing is another process controlled by lncRNAs.5Article, see p 699Malat1/Neat2, one of the first characterized lncRNAs, participates in alternative splicing by controlling the phosphorylation of serine/arginine-rich proteins, a well-characterized family of splicing factors.6 In the heart, other lncRNAs such as circular RNAs derived from the titin gene enable the splicing factors RBM20 (RNA binding motif protein 20) and serine/arginine-rich splicing factor 10 to properly splice important cardiac genes, including Casq2 or Camk2d.7In this issue of Circulation, Zhao et al8 uncover the function of the cardiomyocyte-specific lncRNA triadin-antisense (Trdn-as). Trdn-as is encoded within the triadin (Trdn) gene. Triadin is a well-known molecular component of the calcium release unit of the cardiomyocyte. It interacts with the ryanodine receptor and with calsequestrin to enhance the sarcoplasmic reticulum Ca2+ release that couples cell excitation with contraction (Figure). Triadin is composed of 41 exons, which can be alternatively spliced to 4 distinct isoforms that vary between cardiac and skeletal muscle cells. Triadin-1 is the shortest isoform, and it is the predominant one in cardiomyocytes.9,10Download figureDownload PowerPointFigure. Function of the long noncoding RNA Trdn-as proposed by Zhao et al.8 LTCC indicates L-type calcium channel; RYR2, ryanodine receptor 2; SERCA, sarco/endoplasmic reticulum Ca²⁺-ATPase; SR, sarcoplasmic reticulum; SRSF1/10; serine/arginine-rich splicing factor 1/10; Trdn, triadin; and Trdn-as, triadin-antisense.Zhao and colleagues generated Trdn-as knockout (KO) mice that developed reduced ejection fraction and reduced exercise capacity and died prematurely. At the cellular level, isolated adult ventricular cardiomyocytes exhibited increased sarcoplasmic reticulum Ca2+ content and reduced Ca2+ transients on isoproterenol treatment. Moreover, Trdn-as KO mice were prone to premature ventricular contractions and ventricular tachycardia on adrenergic stimulation with isoproterenol, a phenotype reminiscent of catecholaminergic polymorphic ventricular tachycardia. Globally, the phenotype of Trdn-as KO mice resembles the calcium-handling defects observed in Trdn KO mice11 and in patients with the triadin KO syndrome.12 The cardiac isoform of triadin, triadin-1, was greatly reduced in Trdn-as KO mice. Triadin-1 overexpression was sufficient to rescue the Ca2+-handling defects. On the basis of this finding, Zhao et al propose that the function of Trdn-as is to facilitate the splicing of Trdn pre-mRNA to the cardiac triadin-1 isoform (Figure). Forced overexpression of Trdn-as increases triadin-1 expression in their model, and it can do so even in C2C12 cells, a skeletal muscle cell line that does not express Trdn-as. Mechanistically, they demonstrate that Trdn-as interacts with the Trdn pre-mRNA and with the sarcoplasmic reticulum splicing factors serine/arginine-rich splicing factors 1 and 10. Moreover, the interaction of serine/arginine-rich splicing factor 1 with Trdn pre-mRNA as measured by RNA immunoprecipitation was significantly decreased in the absence of Trdn-as, thereby suggesting that Trdn-as is required to correctly splice the cardiac triadin-1 isoform.Previous studies examined the function of the Trdn-as lncRNA. Zhang et al3 already observed a correlation between the expression of Trdn-as and cardiac triadin-1 in the heart. Overexpression of Trdn-as in HL-1 cells induced a small increase in the ratio of cardiac triadin-1 over skeletal triadin-4 (Trdn95). On the basis of these findings, Zhang et al proposed a model in which Trdn-as blocks the formation of the long skeletal triadin-4 in favor of the short cardiac triadin-1 isoform, but these experimental results could very well fit with the Zhao et al model. van Heesch et al2 were able to detect a translated short open reading frame in the human Trdn-as, which could be translated in vitro to an ≈7-kDa microprotein. However, they detected this microprotein in only 2 of 5 human hearts and not in mice. Zhao and colleagues also tried to detect these microproteins, but they found no evidence of them. Thus, the existence of a small protein encoded within Trdn-as remains elusive.From a gene-regulatory point of view, Trdn-as is an example of how a cell-specific lncRNA can control ubiquitously expressed splicing factors to elicit a cell-specific effect. In this case, cardiomyocyte-specific Trdn-as recruits more ubiquitous splicing factors to orchestrate the formation of triadin-1 selectively in cardiomyocytes. Skeletal muscle cells also express Trdn, Srsf1, and Srsf10, but because they do not express Trdn-as, the cardiac triadin-1 isoform is not produced. From a therapeutic perspective, this finding highlights potential new tools to modulate Ca2+ cycling in heart disease. Both Trdn-as lncRNA and cardiac triadin isoform-1 are reduced in heart failure and ventricular arrhythmias.8,13 Speculatively, a therapeutic strategy to target Trdn-as to rescue triadin function and sarcoplasmic reticulum Ca2+ release in these patients, thereby improving systolic function and reducing the proarrhythmogenic spontaneous depolarizations caused by spontaneous Ca2+ release events, could be envisioned.Many other lncRNAs have been shown to be altered in cardiovascular diseases such as heart failure and cardiac hypertrophy. So far, research has focused on the contribution of these lncRNAs to disease. However, how the expression of these lncRNAs is regulated remains poorly understood in most cases. As in the regulation of coding mRNAs, lncRNAs can be controlled at the transcriptional and posttranscriptional levels by transcription factors, epigenetic modifications, microRNAs, and many other mechanisms. The lncRNA Myheart (Mhrt) is one of the few examples whose regulation has been examined in the heart.14Mhrt stands for Myh-associated RNA transcripts and refers to several antisense transcripts encoded within the Myh7 loci. Mhrt is highly expressed in the adult heart, and it inhibits the prohypertrophic chromatin-remodeling factor BRG1. On pressure overload, activation of the stress-induced complex BRG1-HDAC-PARP represses the Mhrt promoter and reduces its expression. Thus, Mhrt governs negative feedback with BRG1 that prevents cardiac hypertrophy until there is a pathological stressor. Little is known about other mechanisms that regulate lncRNAs in the heart, including Trdn-as. Further research is required to understand whether these lncRNAs just contribute to disease or whether they are part of a compensatory response.The regulation of Trdn by Trdn-as raises the question of whether other cardiac antisense lncRNAs regulate splicing. To address this at the whole-transcriptome level, it would be of great value to develop a global picture of all the intermolecular RNA interactions occurring in the heart in vivo. It is already possible to capture and measure RNA–RNA interactions with high-throughput technologies such as RNA in situ conformation sequencing.15 RNA in situ conformation sequencing captures RNA–RNA interactions by crosslinking RNA molecules that are in physical proximity to each other. After several steps, chimeric RNA fragments can be sequenced to identify how RNAs interact with each other at single-nucleotide resolution. Mapping the lncRNA interactome will guide us in the study of uncharacterized lncRNAs, and it will tell us whether the control of splicing by antisense lncRNAs constitutes a general biological principle that applies to other cardiac genes.In conclusion, lncRNAs are recently recognized players in the regulation of alternative splicing in the heart. The field is just starting to characterize some of them, but a great deal of additional research is needed to develop a more comprehensive view of all their functions. Unraveling new lncRNAs such as Trdn-as will foster a much deeper understanding of gene regulation in the heart, and it will provide new targets to expand therapeutic options in cardiovascular disease.Article InformationSources of FundingNone.Disclosures Dr Pinto serves as consultant for biotech and pharmaceutical companies that develop molecules that target myocardial disease, including catecholaminergic polymorphic ventricular tachycardia. Dr Pinto is inventor on patents related to cardiomyopathy and holds minor shares (<5%) in a spin-off aimed at developing therapies for heart disease. Mr Montañés-Agudo reports no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 717.Correspondence to: Yigal M. Pinto, MD, PhD, Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. Email y.[email protected]nlReferences1. Statello L, Guo C-J, Chen L-L, Huarte M. Gene regulation by long non-coding RNAs and its biological functions.Nat Rev Mol Cell Biol. 2021; 22:96–118. doi: 10.1038/s41580-020-00315-9CrossrefMedlineGoogle Scholar2. van Heesch S, Witte F, Schneider-Lunitz V, Schulz JF, Adami E, Faber AB, Kirchner M, Maatz H, Blachut S, Sandmann C-L, et al. The translational landscape of the human heart.Cell. 2019; 178:242–260.e29. doi: 10.1016/j.cell.2019.05.010CrossrefMedlineGoogle Scholar3. Frankish A, Diekhans M, Ferreira A-M, Johnson R, Jungreis I, Loveland J, Mudge JM, Sisu C, Wright J, Armstrong J, et al. GENCODE reference annotation for the human and mouse genomes.Nucleic Acids Res. 2019; 47:D766–D773. doi: 10.1093/nar/gky955CrossrefMedlineGoogle Scholar4. Papait R, Kunderfranco P, Stirparo GG, Latronico MVG, Condorelli G. Long noncoding RNA: a new player of heart failure?J Cardiovasc Transl Res. 2013; 6:876–883. doi: 10.1007/s12265-013-9488-6CrossrefMedlineGoogle Scholar5. Pisignano G, Ladomery M. Epigenetic regulation of alternative splicing: how lncRNAs tailor the message.Noncoding RNA. 2021; 7:21. doi: 10.3390/ncrna701002MedlineGoogle Scholar6. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.Mol Cell. 2010; 39:925–938. doi: 10.1016/j.molcel.2010.08.011CrossrefMedlineGoogle Scholar7. Tijsen AJ, Cócera Ortega L, Reckman YJ, Zhang X, van der Made I, Aufiero S, Li J, Kamps SC, van den Bout A, Devalla HD, et al. Titin circular RNAs create a back-splice motif essential for SRSF10 splicing.Circulation. 2021; 143:1502–1512. doi: 10.1161/CIRCULATIONAHA.120.050455LinkGoogle Scholar8. Zhao Y, Riching AS, Knight WE, Chi C, Broadwell LJ, Du Y, Abdel-Hafiz M, Ambardekar AV, Irwin DC, Proenza C, et al. Cardiomyocyte-specific long noncoding RNA regulates alternative splicing of the Triadin gene in the heart.Circulation. 2022; 146:699–714. doi: 10.1161/CIRCULATIONAHA.121.058017LinkGoogle Scholar9. Chopra N, Knollmann BC. Triadin regulates cardiac muscle couplon structure and microdomain Ca2+ signalling: a path towards ventricular arrhythmias.Cardiovasc Res. 2013; 98:187–191. doi: 10.1093/cvr/cvt023CrossrefMedlineGoogle Scholar10. Marty I, Fauré J, Fourest-Lieuvin A, Vassilopoulos S, Oddoux S, Brocard J. Triadin: what possible function 20 years later?J Physiol. 2009; 587:3117–3121. doi: 10.1113/jphysiol.2009.171892CrossrefMedlineGoogle Scholar11. Chopra N, Yang T, Asghari P, Moore ED, Huke S, Akin B, Cattolica RA, Perez CF, Hlaing T, Knollmann-Ritschel BEC, et al. Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation–contraction coupling, and cardiac arrhythmias.Proc Natl Acad Sci. 2009; 106:7636–7641. doi: 10.1073/pnas.0902919106CrossrefMedlineGoogle Scholar12. Hancox JC, James AF, Walsh MA, Stuart AG. Triadin mutations: a cause of ventricular arrhythmias in children and young adults.J Congenit Cardiol. 2017; 1:9. doi: 10.1186/s40949-017-0011-9CrossrefGoogle Scholar13. Zhang L, Salgado-Somoza A, Vausort M, Leszek P, Devaux Y. A heart-enriched antisense long non-coding RNA regulates the balance between cardiac and skeletal muscle triadin.Biochim Biophys Acta Mol Cell Res. 2018; 1865:247–258. doi: 10.1016/j.bbamcr.2017.11.002CrossrefMedlineGoogle Scholar14. Han P, Li W, Lin C-H, Yang J, Shang C, Nuernberg ST, Jin KK, Xu W, Lin C-Y, Lin C-J, et al. A long noncoding RNA protects the heart from pathological hypertrophy.Nature. 2014; 514:102–106. doi: 10.1038/nature13596CrossrefMedlineGoogle Scholar15. Cai Z, Cao C, Ji L, Ye R, Wang D, Xia C, Wang S, Du Z, Hu N, Yu X, et al. RIC-seq for global in situ profiling of RNA–RNA spatial interactions.Nature. 2020; 582:432–437. doi: 10.1038/s41586-020-2249-1CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails August 30, 2022Vol 146, Issue 9 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.061232PMID: 36037268 Originally publishedAugust 29, 2022 KeywordsRNA, long noncodingRNA splicingEditorialsPDF download Advertisement SubjectsArrhythmiasCalcium Cycling/Excitation-Contraction CouplingGene Expression and RegulationGenetically Altered and Transgenic ModelsHeart Failure" @default.
• W4293490614 created "2022-08-29" @default.
• W4293490614 creator A5051757265 @default.
• W4293490614 creator A5061943173 @default.
• W4293490614 date "2022-08-30" @default.
• W4293490614 modified "2023-10-18" @default.
• W4293490614 title "Triadin-Antisense: An lncRNA in the Backstage of Cardiac Alternative Splicing" @default.
• W4293490614 cites W1995777485 @default.
• W4293490614 cites W2016093464 @default.
• W4293490614 cites W2058970225 @default.
• W4293490614 cites W2114329647 @default.
• W4293490614 cites W2118322705 @default.
• W4293490614 cites W2172206705 @default.
• W4293490614 cites W2765844855 @default.
• W4293490614 cites W2767724609 @default.
• W4293490614 cites W2898598946 @default.
• W4293490614 cites W2947880448 @default.
• W4293490614 cites W3022604539 @default.
• W4293490614 cites W3115880421 @default.
• W4293490614 cites W3129653965 @default.
• W4293490614 cites W3134512236 @default.
• W4293490614 cites W4286588519 @default.
• W4293490614 doi "https://doi.org/10.1161/circulationaha.122.061232" @default.
• W4293490614 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36037268" @default.
• W4293490614 hasPublicationYear "2022" @default.
• W4293490614 type Work @default.
• W4293490614 citedByCount "0" @default.
• W4293490614 crossrefType "journal-article" @default.
• W4293490614 hasAuthorship W4293490614A5051757265 @default.
• W4293490614 hasAuthorship W4293490614A5061943173 @default.
• W4293490614 hasBestOaLocation W42934906141 @default.
• W4293490614 hasConcept C104317684 @default.
• W4293490614 hasConcept C194583182 @default.
• W4293490614 hasConcept C36823959 @default.
• W4293490614 hasConcept C54355233 @default.
• W4293490614 hasConcept C54458228 @default.
• W4293490614 hasConcept C67705224 @default.
• W4293490614 hasConcept C70721500 @default.
• W4293490614 hasConcept C71924100 @default.
• W4293490614 hasConcept C86803240 @default.
• W4293490614 hasConceptScore W4293490614C104317684 @default.
• W4293490614 hasConceptScore W4293490614C194583182 @default.
• W4293490614 hasConceptScore W4293490614C36823959 @default.
• W4293490614 hasConceptScore W4293490614C54355233 @default.
• W4293490614 hasConceptScore W4293490614C54458228 @default.
• W4293490614 hasConceptScore W4293490614C67705224 @default.
• W4293490614 hasConceptScore W4293490614C70721500 @default.
• W4293490614 hasConceptScore W4293490614C71924100 @default.
• W4293490614 hasConceptScore W4293490614C86803240 @default.
• W4293490614 hasIssue "9" @default.
• W4293490614 hasLocation W42934906141 @default.
• W4293490614 hasLocation W42934906142 @default.
• W4293490614 hasOpenAccess W4293490614 @default.
• W4293490614 hasPrimaryLocation W42934906141 @default.
• W4293490614 hasRelatedWork W2013274463 @default.
• W4293490614 hasRelatedWork W2152297627 @default.
• W4293490614 hasRelatedWork W2338415055 @default.
• W4293490614 hasRelatedWork W2885403345 @default.
• W4293490614 hasRelatedWork W2979636931 @default.
• W4293490614 hasRelatedWork W3216301189 @default.
• W4293490614 hasRelatedWork W4200067160 @default.
• W4293490614 hasRelatedWork W4200624300 @default.
• W4293490614 hasRelatedWork W4253826539 @default.
• W4293490614 hasRelatedWork W2135103820 @default.
• W4293490614 hasVolume "146" @default.
• W4293490614 isParatext "false" @default.
• W4293490614 isRetracted "false" @default.
• W4293490614 workType "article" @default.