Long noncoding RNAs in cardiac development and ageing

Key Points

  • Long noncoding RNAs (lncRNAs) comprise a vast family of noncoding RNAs that regulate gene expression through various epigenetic mechanisms mainly related to chromatin regulation

  • LncRNAs regulate multiple biological pathways in the heart

  • Deep RNA sequencing has identified hundreds of lncRNAs that are dysregulated in diseased hearts, although this change does not necessarily imply a functional effect

  • LncRNAs control the differentiation of pluripotent stem cells and cardiac precursors into cardiomyocytes and, therefore, might be useful for cardiac regeneration

  • LncRNAs are involved in cellular senescence and might be used to limit ageing-associated disease processes

  • The therapeutic or biomarker utility of lncRNAs remains to be validated

Abstract

A large part of the mammalian genome is transcribed into noncoding RNAs. Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators of gene expression. Distinct molecular mechanisms allow lncRNAs either to activate or to repress gene expression, thereby participating in the regulation of cellular and tissue function. LncRNAs, therefore, have important roles in healthy and diseased hearts, and might be targets for therapeutic intervention. In this Review, we summarize the current knowledge of the roles of lncRNAs in cardiac development and ageing. After describing the definition and classification of lncRNAs, we present an overview of the mechanisms by which lncRNAs regulate gene expression. We discuss the multiple roles of lncRNAs in the heart, and focus on the regulation of embryonic stem cell differentiation, cardiac cell fate and development, and cardiac ageing. We emphasize the importance of chromatin remodelling in this regulation. Finally, we discuss the therapeutic and biomarker potential of lncRNAs.

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Figure 1: Classification of lncRNAs according to their genomic location.
Figure 2: Mechanisms of action of lncRNAs.
Figure 3: Regulation of cardiac pathways by lncRNAs.
Figure 4: Mhrt inhibits chromatin targeting and gene regulation by Brg1.

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Acknowledgements

The authors are writing on behalf of the Cardiolinc network (http://www.cardiolinc.org/). Y.D. is supported by the Ministry of Higher Education and Research and the National Research Fund of Luxembourg. J.Z. has received a fellowship from the National Research Fund of Luxembourg (grant PhD-AFR 3972501). C.-P.C. is supported by the NIH (HL118087, HL121197), the AHA (Established Investigator Award 12EIA8960018), March of Dimes Foundation (#6-FY11-260), Indiana University (IU) School of Medicine—IU Health Strategic Research Initiative, and the IU Physician–Scientist Initiative, endowed by Lilly Endowment. G.W.D. is supported by a grant from the NIH (R01 HL108943). S.H. is supported by the European Union Commission's Seventh Framework programme under grant agreement N°305507 (HOMAGE), N°602904 (FIBROTARGETS), N°261409 (MEDIA), N°278249 (EU MASCARA), N°602156 (HECATOS), and the Marie-Curie Industry Academy Pathways and Partnerships (CARDIOMIR) N°285991. We acknowledge the Netherlands Heart Foundation, the Netherlands Organization for Scientific Research (KNAW), and the Royal Dutch Academy of Sciences (KNAW) for funding the concerted research activity of CVON Arena.

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All the authors researched data for the article, discussed its contents, and wrote the manuscript. Y.D. and S.H. reviewed and edited the manuscript before submission.

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Correspondence to Yvan Devaux.

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Devaux, Y., Zangrando, J., Schroen, B. et al. Long noncoding RNAs in cardiac development and ageing. Nat Rev Cardiol 12, 415–425 (2015). https://doi.org/10.1038/nrcardio.2015.55

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