The Smooth Long Noncoding RNA SENCR
2014; Lippincott Williams & Wilkins; Volume: 34; Issue: 6 Linguagem: Inglês
10.1161/atvbaha.114.303504
ISSN1524-4636
AutoresThomas Thum, Regalla Kumarswamy,
Tópico(s)Circular RNAs in diseases
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 34, No. 6The Smooth Long Noncoding RNA SENCR Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Smooth Long Noncoding RNA SENCR Thomas Thum and Regalla Kumarswamy Thomas ThumThomas Thum From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integrated Research and Treatment Center Transplantation (T.T., R.K.) and Excellence Cluster REBIRTH (T.T.), Hannover Medical School, Hannover, Germany; and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.). and Regalla KumarswamyRegalla Kumarswamy From the Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integrated Research and Treatment Center Transplantation (T.T., R.K.) and Excellence Cluster REBIRTH (T.T.), Hannover Medical School, Hannover, Germany; and National Heart and Lung Institute, Imperial College London, London, United Kingdom (T.T.). Originally published1 Jun 2014https://doi.org/10.1161/ATVBAHA.114.303504Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;34:1124–1125Long noncoding RNAs (lncRNAs) have emerged as novel regulators of gene expression, but their mode of action is diverse and ill understood. There are few examples that lncRNAs are also involved in cardiovascular development as well as in cardiovascular (patho)physiology (Figure). An lncRNA called Braveheart was recently shown to be crucial for cardiac development. Braveheart is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1, a master regulator of a common multipotent cardiovascular progenitor.1 Another lncRNA Fendrr was shown to control chromatin modifications and thereby control developmental signaling in the heart.2 Evidence for a role of lncRNAs in cardiomyocytes comes from a third study that studied interactions between the lncRNA CHRF and a microRNA named microRNA-489.3 Recently, an elegant article also provided first evidence for the lncRNA MALAT1 to be enriched in endothelial cells and to control endothelial functions such as migration and vascular sprouting,4 although it is likely that this lncRNA also has important functions in other cardiovascular cell types. Finally, in analogy to microRNAs, another study showed that certain lncRNAs, such as LIPCAR, may also circulate in the bloodstream and could serve as powerful diagnostic and prognostic markers of cardiovascular diseases such as heart failure.5Download figureDownload PowerPointFigure. Recently identified long noncoding RNAs (lncRNAs) of cardiovascular importance. BVHT indicates Braveheart; ES, embryonic stem cells; and HF, heart failure.See accompanying article on page 1249In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Bell et al6 add to the growing knowledge about the cardiovascular functions of lncRNAs with a novel approach and finding; they used RNA sequencing of human coronary artery smooth muscle cells and identified several unannotated lncRNAs. Of this list, they pinpointed a vascular cell–enriched lncRNA that they termed smooth muscle and endothelial cell–enriched migration/differentiation-associated long noncoding RNA, or in short SENCR, which is selectively expressed in specific tissues and cell lines. Further characterization revealed that the gene encoding for SENCR comprises 3 exons and is placed in antisense orientation in one of the introns of a protein-coding gene called Friend leukemia virus integration 1 (FLI1). Expression of SENCR and FLI1 correlates with each other in various tissues, implying that both these transcripts share a common transcriptional regulatory mechanism. Spatial presence of lncRNAs within the cell generally depends on the function that they have to perform. In situ hybridization experiments and cell fractionation studies revealed that SENCR is a cytosolic transcript, indicating that SENCR is a cis-acting element. Consistent with this, knockdown of SENCR with small interfering RNA has little or no effect on neighboring genes including FLI1. To understand the potential function of SENCR, the authors performed RNA sequencing–based transcriptome analysis of smooth muscle cells after small interfering RNA–mediated suppression of SENCR. Interestingly, expression of many contractile genes was deregulated on SENCR silencing. Importantly, MYOCD, which is a key transcriptional regulator of the smooth muscle cell contractile gene expression, was downregulated on SENCR silencing. Concomitant with suppression of smooth muscle cell contractile gene expression, SENCR silencing also upregulated several genes associated with cell migration. Consistent with this, attenuation of SENCR expression resulted in hypermotile phenotype of human smooth muscle cells.Although coexpression of FLI1 and SENCR was noted, the exact mechanism how these RNAs are transcriptionally controlled is not clear. Based on a previous finding about the undetectable FLI1 promoter activity in cells expressing high levels of FLI1 mRNA, the authors speculate that a remotely acting enhancer element might be critical for transcription of SENCR and FLI1. As a potential mechanism of action of SENCR, the authors propose that SENCR sponges a low abundant microRNA that otherwise would function to regulate the smooth muscle cell contractile gene program. However, the likelihood of this function is relatively weak in view of low abundance of SENCR (0.8 copies/cell). Other underlying mechanisms thus need to be explored by future experiments.In general, the results of this study indicate that lncRNAs, albeit expressed at low levels, perform important functions in vascular cells. Although robust methodologies including RNA sequencing analysis strengthen the conclusions of this study, further studies are clearly needed to delineate the exact mechanism how SENCR modulates MYCD (myocardin) and other gene networks and to understand the role of FLI1 in smooth muscle cells and potentially other cell types.Source of FundingThe authors have financial support from the IFB-Tx (Bundesministerium für Bildung und Forschung - BMBF; T. Thum), Deutsche Forschungsgemeinschaft (DFG) (TH 903/11-1; T. Thum, RE3523/1-1; R. Kumarswamy), and Fondation Leducq (T. Thum).DisclosuresNone.FootnotesCorrespondence to Thomas Thum, MD, PhD, Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany. E-mail [email protected]References1. Klattenhoff CA, Scheuermann JC, Surface LE, Bradley RK, Fields PA, Steinhauser ML, Ding H, Butty VL, Torrey L, Haas S, Abo R, Tabebordbar M, Lee RT, Burge CB, Boyer LA. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.Cell. 2013; 152:570–583.CrossrefMedlineGoogle Scholar2. Grote P, Wittler L, Hendrix D, Koch F, Währisch S, Beisaw A, Macura K, Bläss G, Kellis M, Werber M, Herrmann BG. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse.Dev Cell. 2013; 24:206–214.CrossrefMedlineGoogle Scholar3. Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res. 2014; 114:1377–1388.LinkGoogle Scholar4. Michalik KM, You X, Manavski Y, Doddaballapur A, Zörnig M, Braun T, John D, Ponomareva Y, Chen W, Uchida S, Boon RA, Dimmeler S. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth.Circ Res. 2014; 114:1389–1397.LinkGoogle Scholar5. Kumarswamy R, Bauters C, Volkmann I, Maury F, Fetisch J, Holzmann A, Lemesle G, Degroote P, Pinet F, Thum T. The circulating long non-coding RNA LIPCAR predicts survival in heart failure patients [published online ahead of print March 24, 2014].Circ Res. doi: 10.1161/CIRCRESAHA.114.303915. http://circres.ahajournals.org/content/early/2014/03/24/CIRCRESAHA.114.303915.long. Accessed April 17, 2014.Google Scholar6. Bell RD, Long X, Lin M, Bergmann JH, Nanda V, Cowan SL, Zhou Q, Han Y, Spector DL, Zheng D, Miano JM. Identification and initial functional characterization of a human vascular cell–enriched long noncoding RNA.Arterioscler Thromb Vasc Biol. 2014; 34:1249–1259.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fasolo F, Paloschi V and Maegdefessel L (2022) Long non-coding RNAs at the crossroad of vascular smooth muscle cell phenotypic modulation in atherosclerosis and neointimal formation, Atherosclerosis, 10.1016/j.atherosclerosis.2022.11.021, Online publication date: 1-Dec-2022. 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Rizki G and Boyer L (2015) Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease, Circulation Research, 117:2, (192-206), Online publication date: 3-Jul-2015. June 2014Vol 34, Issue 6 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.114.303504PMID: 24828518 Originally publishedJune 1, 2014 KeywordsRNA, long noncodingEditorialsmyocytes, smooth muscle cellsPDF download Advertisement
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