Abstract
Long noncoding RNAs have gained widespread attention in recent years for their crucial role in biological regulation. They have been implicated in a range of developmental processes and diseases including cancer, cardiovascular, and neuronal diseases. However, the role of long noncoding RNAs (lncRNAs) in left ventricular noncompaction (LVNC) has not been explored. In this study, we investigated the expression levels of lncRNAs in the blood of LVNC patients and healthy subjects to identify differentially expressed lncRNA that develop LVNC specific biomarkers and targets for developing therapies using biological pathways. We used Agilent Human lncRNA array that contains both updated lncRNAs and mRNAs probes. We identified 1,568 upregulated and 1,141 downregulated (log fold-change > 2.0) lncRNAs that are differentially expressed between LVNC and the control group. Among them, RP11-1100L3.7 and XLOC_002730 are the most upregulated and downregulated lncRNAs. Using quantitative real-time reverse transcription polymerase chain reaction (RT-QPCR), we confirmed the differential expression of three top upregulated and downregulated lncRNAs along with two other randomly picked lncRNAs. Gene Ontology (GO) and KEGG pathways analysis with these differentially expressed lncRNAs provide insight into the cellular pathway leading to LVNC pathogenesis. We also identified 1,066 upregulated and 1,017 downregulated mRNAs. Gene set enrichment analysis (GSEA) showed that G2M, Estrogen, and inflammatory pathways are enriched in differentially expressed genes (DEG). We also identified miRNA targets for these differentially expressed genes. In this study, we first report the use of LncRNA microarray to understand the pathogenesis of LVNC and to identify several lncRNA and genes and their targets as potential biomarkers.
Highlights
Left ventricular noncompaction is a rare disease that is characterized by the failure of densification in the normal embryonic cardiac tissue
We found that the highest Gene Ontology (GO) classification targeted by underregulated transcripts were intracellular signal transduction (BP), plasma membrane (CC), and enzyme binding (MF) (Figures 3A–C)
Noncompaction of the myocardium is seen in association with other congenital cardiac abnormalities, it can occur as a primary disorder in the absence of other structural heart diseases [3]
Summary
Left ventricular noncompaction is a rare disease that is characterized by the failure of densification in the normal embryonic cardiac tissue. It can occur in isolation or association with congenital heart defects (CHDs), neuromuscular disorders, and systemic heart anomalies [1, 2]. Left ventricular noncompaction is a genetically heterogeneous disease [5] and is associated with genes and/or proteins that are involved in sarcomere (MYH7, ACTC, MYBPC3, TNNT2), cytoskeletal (ZASP, LMNA), and mitochondrial structure or function (TAZ) [6,7,8,9]. Using exome and mitochondrial DNA sequencing from myocardial tissue samples, Liu Z et al identified mutations in 16S rRNA 2336T>C mitochondrial mutation but did not detect any pathogenic mutations in TNNT2 and MYBPC3 genes [10]
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