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      Long noncoding RNA Chast promotes cardiac remodeling.

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          Abstract

          Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases.

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          Most cited references20

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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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            Cardiac plasticity.

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              A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial-mesenchymal transition.

              Expression of Snail1 in epithelial cells triggers an epithelial-mesenchymal transition (EMT). Here, we demonstrate that the synthesis of Zeb2, a transcriptional repressor of E-cadherin, is up-regulated after Snail1-induced EMT. Snail1 does not affect the synthesis of Zeb2 mRNA, but prevents the processing of a large intron located in its 5'-untranslated region (UTR). This intron contains an internal ribosome entry site (IRES) necessary for the expression of Zeb2. Maintenance of 5'-UTR Zeb2 intron is dependent on the expression of a natural antisense transcript (NAT) that overlaps the 5' splice site in the intron. Ectopic overexpression of this NAT in epithelial cells prevents splicing of the Zeb2 5'-UTR, increases the levels of Zeb2 protein, and consequently down-regulates E-cadherin mRNA and protein. The relevance of these results is demonstrated by the strong association between NAT presence and conservation of the 5'-UTR intron in cells that have undergone EMT or in human tumors with low E-cadherin expression. Therefore, the results presented in this article reveal the existence of a NAT capable of activating Zeb2 expression, explain the mechanism involved in this activation, and demonstrate that this NAT regulates E-cadherin expression.
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                Author and article information

                Journal
                Sci Transl Med
                Science translational medicine
                1946-6242
                1946-6234
                Feb 17 2016
                : 8
                : 326
                Affiliations
                [1 ] Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany. Excellence Cluster REBIRTH, Hannover Medical School, D-30625 Hannover, Germany.
                [2 ] Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany.
                [3 ] Institute of Pharmacology and Toxicology, Technical University of Munich, D-80802 Munich, Germany. German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, D-80802 Munich, Germany.
                [4 ] Department of Bioinformatics, University of Würzburg, D-97074 Würzburg, Germany.
                [5 ] Department of Bioinformatics, University of Würzburg, D-97074 Würzburg, Germany. Institute of Human Genetics, University of Würzburg, D-97074 Würzburg, Germany.
                [6 ] Institute of Experimental Hematology, Hannover Medical School, D-30625 Hannover, Germany.
                [7 ] Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, D-30625 Hannover, Germany.
                [8 ] Department of Cardiology, Julius-Maximilians University, D-97080 Würzburg, Germany. Comprehensive Heart Failure Center, University of Würzburg, D-97078 Würzburg, Germany.
                [9 ] Department of Cardiology, Maastricht University, 6202 AZ Maastricht, Netherlands.
                [10 ] Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Integriertes Forschungs- und Behandlungszentrum Transplantation (IFB-Tx), Hannover Medical School, D-30625 Hannover, Germany. Excellence Cluster REBIRTH, Hannover Medical School, D-30625 Hannover, Germany. National Heart and Lung Institute, Imperial College London, SW3 6NP London, UK. thum.thomas@mh-hannover.de.
                Article
                8/326/326ra22
                10.1126/scitranslmed.aaf1475
                26888430
                32316c04-2125-4572-883d-00ec898b7467
                Copyright © 2016, American Association for the Advancement of Science.

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