Besides Imprinting
2017; Lippincott Williams & Wilkins; Volume: 121; Issue: 5 Linguagem: Espanhol
10.1161/circresaha.117.311542
ISSN1524-4571
Autores Tópico(s)MicroRNA in disease regulation
ResumoHomeCirculation ResearchVol. 121, No. 5Besides Imprinting Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBBesides ImprintingMeg3 Regulates Cardiac Remodeling in Cardiac Hypertrophy Shizuka Uchida Shizuka UchidaShizuka Uchida From the Cardiovascular Innovation Institute, University of Louisville, KY. Originally published18 Aug 2017https://doi.org/10.1161/CIRCRESAHA.117.311542Circulation Research. 2017;121:486–487It is now firmly recognized that although the majority of mammalian genome is transcribed to RNA, protein-coding transcripts occupy only a minor part of mammalian transcriptome. Instead, increasing evidence suggests that the majority of mammalian RNAs is comprised noncoding RNAs (ncRNAs). ncRNAs are a diverse class of RNAs with many subclasses involved in a wide variety of physiological functions, including those in the heart. Although the functions of small RNAs, including microRNAs, have been elucidated in the past 2 decades, those of longer ncRNAs are increasing being investigated in various fields of studies, including cardiovascular medicine. Among longer ncRNAs, those longer than 200 nucleotides are classified as long noncoding RNAs (lncRNAs). Numerous screening studies have identified several thousand lncRNAs expressed in the heart using microarrays and next-generation sequencing (eg, RNA sequencing), yet only handful have been characterized.1 This lack of characterized lncRNAs is partially because of the low sequence conservation of lncRNAs, making it difficult to translate screening of lncRNAs in humans (eg, patients with cardiovascular disease versus healthy donors) to model organisms (eg, mice, rat, and zebrafish) to study the target lncRNAs in vivo because homologs of lncRNAs cannot easily be identified. However, some well-conserved lncRNAs do exist among humans and other organisms, especially those that are involved in genomic imprinting, which is an epigenetic phenomenon whereby genes are expressed in a parent-of-origin dependent manner.2 Although their function in imprinting is well characterized, the functions outside of imprinting are still under investigation, which should broaden our understanding of lncRNAs in general and especially in the heart in relation to cardiovascular disease in the hope of understanding yet unsolved pathogenesis of cardiovascular disease.Article, see p 575In this new study by Piccoli et al,3 the authors investigated the function of the genomic imprinting gene Meg3 (maternally expressed 3) in cardiac fibroblasts during cardiac remodeling initiated by pathological hypertrophy. First, the authors performed a microarray-based screening to identify differentially expressed lncRNAs in hypertrophied cardiac fibroblasts isolated from mice challenged with transverse aortic constriction (TAC) versus sham-operated mice. From 1425 differentially expressed lncRNAs, the authors applied bioinformatic filters and performed follow-up validation experiments to identify 1 lncRNA Meg3. According to the authors, Meg3 is enriched in cardiac fibroblasts and significantly deregulated in TAC cardiac fibroblasts compared with those of sham. To understand the function of Meg3 in cardiac fibroblasts, the authors conducted a loss-of-function experiment using LNA GapmeR and readout the molecular signatures via microarrays, which identified 3026 differentially regulated genes. From the microarray data, the authors focused on the downregulated gene Mmp-2, a well-known fibrogenic factor induced by TGF-β I (transforming growth factor). Mechanistically, the authors demonstrated that Meg3 directly binds P53, which binds to the Mmp-2 promoter to control the expression of Mmp-2 through TGF-β I. To confirm the findings in vitro, the authors silenced Meg3 in vivo by LNA GapmeR and performed the TAC operation. Compared with the sham-operated hearts, TAC-induced Mmp-2 expression and its active cleaved form were inhibited, which coincided with the decreased fibrosis and hypertrophic growth of cardiomyocytes. These in vivo findings were independently confirmed by inducing isolated neonatal rat cardiomyocytes with a conditioned medium from Meg3-silenced cardiac fibroblasts.Taken together, this study clearly indicates the important function of Meg3 in cardiac fibroblasts during cardiac remodeling initiated by pathological hypertrophy (Figure A). The findings are in line with the known functions of Meg3 in cancer, which is to assist the binding of P53 to the promoters of other genes.4 Another previous study in human induced pluripotent stem cells indicates the binding of Meg3 to epigenetic factors Ezh2 (a component of polycomb repressive complex-2) and Jarid2,5 suggesting that Meg3 actively controls the transcription of several genes (Figure B). This mechanism of action is reflected by the transcriptome analysis of Piccoli et al3 because there are many differentially expressed genes identified on the silencing of Meg3. Because an overexpression of Meg3 downregulates the P53-specific E3 ubiquitin ligase MDM2 (mouse double minute 2), which in turn induces the accumulation of P53 in a cancer cell line,4 and MDM2 binds to Ezh2 in mouse-induced pluripotent stem cells,6 it is of interest to understand how many proteins Meg3 binds to and whether such binding makes an attractive model to understand the scaffolding of lncRNAs in general.7Download figureDownload PowerPointFigure. Functions of Meg3 (maternally expressed 3).A, Extracellular matrix (ECM) remodeling via Meg3. Meg3 binds to P53 to assist the TGF-β (transforming growth factor)–induced binding of P53 to the promoter of Mmp-2, which contributes to the ECM remodeling. B, Meg3 in cancer and human induced pluripotent stem cells. Meg3 directly binds to P53 and a component of polycomb repressive complex-2 (PRC2; ie, Ezh2) to control transcriptions of genes. The Meg3-P53 axis is controlled, in part, by the suppression of a P53-specific E3 ubiquitin ligase MDM2 (mouse double minute 2).Although Piccoli et al3 were able to pinpoint 1 lncRNA Meg3, there are 1425 differentially expressed lncRNAs in hypertrophied cardiac fibroblasts compared with the control. The obvious question is whether other lncRNAs are also contributing to the cardiac fibrosis. The authors applied bioinformatic filters to narrow down the list of differentially expressed lncRNAs. However, there are still more than a handful of lncRNAs remaining in the short list. Thus, the transcriptomics data disclosed in this publication should serve as a cherry picking list for further functional studies.As pointed out by several researchers, an acute knockdown method is rather error prone; thus, it is preferred that genomic deletion studies should be performed to confirm the findings.8 Because Meg3 knockout mice have been published,9–11 an obvious follow-up study is to challenge Meg3 knockout mice with TAC. However, the locus harboring Meg3 is complicated, which also interferes the expression of nearby genes (eg, Dlk1, Rian/Meg8). Furthermore, along with 10 isoforms of Meg3, Meg3 is a host of 2 microRNAs, miR-673 and miR-770. Given such biological background, Piccoli et al3 extended their study to measure the expressions of these microRNAs, which were not affected by the post-transcriptional silencing of Meg3. However, the extent to which Meg3 exerts its action in cis has not been discussed. It is known that the Meg3-nearby gene Dlk1 (δ-like 1 homolog) promotes the activation of hepatic stellate cells during chronic liver injury to the progression of liver fibrosis.12 Given that Dlk1 directly interacts with NOTCH113 and Notch pathway is known to be involved in cardiac remodeling,14 it is of interest to understand to what extent Meg3 is involved in the regulation of Dlk1 and its relationship to cardiac fibrosis.Because this is the first study uncovering the function of Meg3 in cardiac fibroblasts and its conservation in humans, it is of high hope that the post-transcriptional silencing approach undertaken by Piccoli et al3 may yield a pharmacological intervention of adverse fibrosis during the cardiac remodeling caused by pathological hypertrophy of the heart. Given that Meg3 interacts with epigenetic and transcriptional factors, it can be viewed as a molecular switch to activate or inhibit several genes to affect a variety of signaling pathways, which also opens up a new avenue for RNA therapeutics for cardiovascular disease in the near future.Sources of FundingThis study was supported by the startup funding from the Mansbach Family, the Gheens Foundation, and other generous supporters at the University of Louisville.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Shizuka Uchida, PhD, Cardiovascular Innovation Institute, University of Louisville, 302 E Muhammad Ali Blvd, Louisville, KY 40202. E-mail [email protected]References1. Uchida S, Dimmeler S. Long noncoding RNAs in cardiovascular diseases.Circ Res. 2015; 116:737–750. doi: 10.1161/CIRCRESAHA.116.302521.LinkGoogle Scholar2. Peters J. 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Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.J Exp Med. 2008; 205:3173–3185. doi: 10.1084/jem.20081427.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Li J, Liu W, Peng F, Cao X, Xie X and Peng C (2023) The multifaceted biology of lncR-Meg3 in cardio-cerebrovascular diseases, Frontiers in Genetics, 10.3389/fgene.2023.1132884, 14 Chang S, Wang Y, Xin Y, Wang S, Luo Y, Wang L, Zhang H and Li J (2021) DNA methylation abnormalities of imprinted genes in congenital heart disease: a pilot study, BMC Medical Genomics, 10.1186/s12920-020-00848-0, 14:1, Online publication date: 1-Dec-2021. Li W, Li Y, Cui S, Liu J, Tan L, Xia H and Zhang C (2021) Se alleviates homocysteine‑induced fibrosis in cardiac fibroblasts via downregulation of lncRNA MEG3, Experimental and Therapeutic Medicine, 10.3892/etm.2021.10704, 22:5 Hamilton S, de Cabo R and Bernier M (2020) Maternally expressed gene 3 in metabolic programming, Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 10.1016/j.bbagrm.2019.06.007, 1863:4, (194396), Online publication date: 1-Apr-2020. Xu L, Wang H, Jiang F, Sun H and Zhang D (2020) LncRNA AK045171 protects the heart from cardiac hypertrophy by regulating the SP1/MG53 signalling pathway, Aging, 10.18632/aging.102668, 12:4, (3126-3139), Online publication date: 21-Feb-2020. Zou L, Ma X, Lin S, Wu B, Chen Y and Peng C (2019) Long noncoding RNA-MEG3 contributes to myocardial ischemia–reperfusion injury through suppression of miR-7-5p expression, Bioscience Reports, 10.1042/BSR20190210, 39:8, Online publication date: 30-Aug-2019. 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August 18, 2017Vol 121, Issue 5 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.311542PMID: 28819035 Originally publishedAugust 18, 2017 Keywordsgenomicsextracellular matrixtranscriptomeEditorialsRNA, long noncodingPDF download Advertisement
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