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      Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases

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          Abstract

          Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease.

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          Most cited references48

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          The transcriptional landscape of the mammalian genome.

          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            Ab initio reconstruction of transcriptomes of pluripotent and lineage committed cells reveals gene structures of thousands of lincRNAs

            RNA-Seq provides an unbiased way to study a transcriptome, including both coding and non-coding genes. To date, most RNA-Seq studies have critically depended on existing annotations, and thus focused on expression levels and variation in known transcripts. Here, we present Scripture, a method to reconstruct the transcriptome of a mammalian cell using only RNA-Seq reads and the genome sequence. We apply it to mouse embryonic stem cells, neuronal precursor cells, and lung fibroblasts to accurately reconstruct the full-length gene structures for the vast majority of known expressed genes. We identify substantial variation in protein-coding genes, including thousands of novel 5′-start sites, 3′-ends, and internal coding exons. We then determine the gene structures of over a thousand lincRNA and antisense loci. Our results open the way to direct experimental manipulation of thousands of non-coding RNAs, and demonstrate the power of ab initio reconstruction to render a comprehensive picture of mammalian transcriptomes.
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              Braveheart, a long noncoding RNA required for cardiovascular lineage commitment.

              Long noncoding RNAs (lncRNAs) are often expressed in a development-specific manner, yet little is known about their roles in lineage commitment. Here, we identified Braveheart (Bvht), a heart-associated lncRNA in mouse. Using multiple embryonic stem cell (ESC) differentiation strategies, we show that Bvht is required for progression of nascent mesoderm toward a cardiac fate. We find that Bvht is necessary for activation of a core cardiovascular gene network and functions upstream of mesoderm posterior 1 (MesP1), a master regulator of a common multipotent cardiovascular progenitor. We also show that Bvht interacts with SUZ12, a component of polycomb-repressive complex 2 (PRC2), during cardiomyocyte differentiation, suggesting that Bvht mediates epigenetic regulation of cardiac commitment. Finally, we demonstrate a role for Bvht in maintaining cardiac fate in neonatal cardiomyocytes. Together, our work provides evidence for a long noncoding RNA with critical roles in the establishment of the cardiovascular lineage during mammalian development. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                05 October 2015
                October 2015
                : 16
                : 10
                : 23651-23667
                Affiliations
                [1 ]Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; E-Mails: karcher@ 123456gru.edu (K.A.); adavila@ 123456gru.edu (A.D.); yaotang@ 123456gru.edu (Y.T.)
                [2 ]Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; E-Mails: zbroskova@ 123456gru.edu (Z.B.); abayoumi@ 123456gru.edu (A.S.B.); jteoh@ 123456gru.edu (J.-p.T.); hsu@ 123456gru.edu (H.S.)
                [3 ]Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: ilkim@ 123456gru.edu ; Tel.: +1-706-721-9414; Fax: +1-706-721-9799.
                Article
                ijms-16-23651
                10.3390/ijms161023651
                4632719
                26445043
                b7b5482d-56fc-410a-8a7e-ba90758681b9
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 August 2015
                : 28 September 2015
                Categories
                Review

                Molecular biology
                chromatin,epigenetic regulation,gene regulation,heart disease,non-coding rnas
                Molecular biology
                chromatin, epigenetic regulation, gene regulation, heart disease, non-coding rnas

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