Cardiovascular Research Unit, Luxembourg Health Institute, Luxembourg.
Heart Failure and Transplantology Department, Institute of Cardiology, Warsaw, Poland.
Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):247-258. doi: 10.1016/j.bbamcr.2017.11.002. Epub 2017 Nov 8.
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.
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.
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.
非编码 RNA 在心脏病理生理学中发挥重要作用。最近的研究报告称，长非编码 RNA（lncRNA）在衰竭心脏中失调，但它们如何导致心力衰竭的发展尚不清楚。在这项研究中，我们旨在鉴定富含心脏的 lncRNA，并研究它们在衰竭心脏中的调节和功能。
对 15 个白种人组织的 RNA-seq 数据集的分析允许鉴定出 415 个富含心脏的 lncRNA。53 个 lncRNA 位于基因组中与心脏功能和疾病相关的蛋白质编码基因的附近。对 16 个衰竭人类心脏的第二个 RNA-seq 数据集的分析突出了一个 lncRNA，由于其位于编码三联蛋白（TRDN）的基因的反义位置，我们任意将其命名为 TRDN-AS。与对照心脏相比，TRDN-AS 和心脏 TRDN 的表达在衰竭人类心脏的活检中上调。在衰竭的心脏中，TRDN-AS 与心脏 TRDN 的一种同工型呈正相关，与骨骼肌 TRDN 的同工型呈负相关。鉴定出人类 TRDN-AS 的鼠同源物，并发现其在心脏中富集并定位于心肌细胞的核区室。实验性心肌梗死后，Trdn-AS 的表达以及心脏和骨骼肌同工型之间的比例均下调。在鼠心肌细胞中，使用 CRISPR/dCas9-VPR 系统激活 Trdn-AS 转录增强了 Trdn 的心脏和骨骼肌同工型之间的比例。
lncRNA TRDN-AS 调节三联蛋白的心脏和骨骼肌同工型之间的平衡。这一发现可能对心力衰竭的治疗具有重要意义。
