A heart-enriched antisense long non-coding RNA regulates the balance between cardiac and skeletal muscle triadin

Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):247-258. doi: 10.1016/j.bbamcr.2017.11.002. Epub 2017 Nov 8.

Abstract

Non-coding RNAs play major roles in cardiac pathophysiology. Recent studies reported that long non-coding RNAs (lncRNAs) are dysregulated in the failing heart, but how they contribute to heart failure development is unclear. In this study, we aimed to identify heart-enriched lncRNAs and investigate their regulation and function in the failing heart.

Results: Analysis of a RNA-seq dataset of 15 Caucasian tissues allowed the identification of 415 heart-enriched lncRNAs. Fifty-three lncRNAs were located on the genome in close vicinity to protein-coding genes associated with cardiac function and disease. Analysis of a second RNA-seq dataset of 16 failing human hearts highlighted one lncRNA which we arbitrarily named TRDN-AS due to its localisation in the antisense position of the gene encoding triadin (TRDN). Expression of TRDN-AS and cardiac TRDN was up-regulated in biopsies from failing human hearts compared to control hearts. In failing hearts, TRDN-AS was positively correlated with a cardiac isoform of TRDN and negatively correlated with a skeletal muscle isoform of TRDN. A murine homolog of human TRDN-AS was identified and found to be enriched in the heart and localised in the nuclear compartment of cardiomyocytes. Trdn-AS expression as well as the ratio between cardiac and skeletal muscle isoforms were down-regulated after experimental myocardial infarction. In murine cardiomyocytes, activation of Trdn-AS transcription with the CRISPR/dCas9-VPR system enhanced the ratio between cardiac and skeletal isoforms of Trdn.

Conclusion: The lncRNA TRDN-AS regulates the balance between cardiac and skeletal isoforms of triadin. This finding may have implications for the treatment of heart failure.

Keywords: Cardiac disease; Gene editing; Heart; Heart failure; Long non-coding RNA; RNA sequencing; Regulation of gene expression; Transcription; Triadin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins* / biosynthesis
  • Carrier Proteins* / genetics
  • Databases, Nucleic Acid*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Muscle Proteins* / biosynthesis
  • Muscle Proteins* / genetics
  • Muscle, Skeletal / metabolism*
  • Myocardium / metabolism*
  • Protein Isoforms / biosynthesis
  • Protein Isoforms / genetics
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Protein Isoforms
  • RNA, Long Noncoding
  • TRDN protein, human
  • Trdn protein, mouse