Abstract
MicroRNAs (miRNAs) are a class of non-coding RNAs of ∼22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3′UTR of protein encoding messenger RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease.
Highlights
Beginning with the discovery of lin-4 in C. elegans in 1993 [1] and followed by let-7 in 2000 and its conservation amongst species [2], the importance and universal effect of microRNAs have provoked an explosive field of research. miRNA genes, encoded by the genome, are a class of noncoding RNAs of 21–23 nucleotides in length, which derive from single-stranded RNA precursors [3]
Target recognition is influenced by the secondary structure of regions surrounding the target sequence and the extent of seed sequence complementarity influences whether the miRNA/ mRNA interaction will result in repression and/or deadenylation of the target mRNA. miRNA conservation among species, from plants to animals, as well as their vast biological importance has been firmly established in the past decade [4]. miRNAs are often grouped into families when sharing identical seed sequences and similar mature sequences, most likely targeting common mRNAs, to different extents [5]. miRNAs display a characteristic spatial, temporal and tissue-specific expression profile and have great impact as key regulators in cell differentiation, growth [6], and apoptosis [7,8,9]
While many miRNAs which regulation has been considered a signature of heart failure [18,43,44,45,46,47,48,49,50,51], were confirmed by deep sequencing to be differentially regulated in hypertrophic cardiomyopathy (HCM), only a few could be confirmed using this technique in dilated cardiomyopathy (DCM)
Summary
Beginning with the discovery of lin-4 in C. elegans in 1993 [1] and followed by let-7 in 2000 and its conservation amongst species [2], the importance and universal effect of microRNAs (miRNAs) have provoked an explosive field of research. miRNA genes, encoded by the genome, are a class of noncoding RNAs of 21–23 nucleotides (nt) in length, which derive from single-stranded RNA precursors [3]. MiRNA genes, encoded by the genome, are a class of noncoding RNAs of 21–23 nucleotides (nt) in length, which derive from single-stranded RNA precursors [3] They negatively regulate gene expression by direct binding to the 39 untranslated region (39 UTR) of a target mRNA, leading to its translational repression and/or deadenylation. Changes in cardiac miRNA expression levels have been associated to cardiac stress and development of cardiac hypertrophy in mice, as a result of transverse aortic constriction (TAC) [14], myocardial infarction and specific transgene expression [14,15,16,17,18], and in human endstage heart failure [15,19]. Besides their specific expression patterns, miRNAs exhibit remarkable biostability, allowing their detection in human plasma and serum, and suggesting that miRNAs may become relevant biomarkers in heart failure [13,20]
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