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Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

ABSTRACT: AIM:Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis. METHODS AND RESULTS:We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease. CONCLUSION:These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic.

SUBMITTER: Ounzain S

PROVIDER: S-EPMC4320320 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

Ounzain Samir S Micheletti Rudi R Beckmann Tal T Schroen Blanche B Alexanian Michael M Pezzuto Iole I Crippa Stefania S Nemir Mohamed M Sarre Alexandre A Johnson Rory R Dauvillier Jérôme J Burdet Frédéric F Ibberson Mark M Guigó Roderic R Xenarios Ioannis I Heymans Stephane S Pedrazzini Thierry T

European heart journal 20140430 6

<h4>Aim</h4>Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis.<h4>Methods and results</h4>We annotated the mouse transcri ...[more]

PMID: 24786300

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Project description:Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating various critical physiological and pathological processes, yet limited information is available about lncRNAs expression in acute myocardial infarction (AMI). We aimed to identified differentially expressed lncRNAs in blood samples of patients with AMI to assess their diagnostic value. Differential expression of lncRNAs in peripheral blood mononuclear cells (PBMC) of patients with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) was compared by RNA sequencing method and validated by real-time polymerase chain reaction (PCR). The area under the receiver operating characteristic curve (ROC) was used to evaluate diagnostic accuracy. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of lncRNA-coexpressed mRNAs were conducted to determine the related biological modules and pathological pathways. RNA sequencing data showed that 58 lncRNAs were differentially expressed between NSTEMI patients and STEMI patients, including 42 upregulated lncRNAs and 16 down-regulated lncRNAs. The ROC curves showed that ENST00000508020.2, LNC_001265, LNC_001526, and LNC_002674 could distinguish AMI patients with preferable sensitivity and specificity. GO enrichment analysis of lncRNA-coexpressed mRNAs indicated that the biological modules were correlated with cell adhesion, calcium ion homeostasis, complement receptor mediated signaling pathway, and immune system process. KEGG pathway analysis indicated that the lncRNAs-co-expressed mRNAs were involved in the regulation of peroxisome proliferators-activated receptors (PPAR) signaling pathway, mTOR signaling pathway, Insulin signaling pathway, HIF-1 signaling, and chemokin signaling pathway. Our results are in line with the previous findings, suggesting that differential expression of lncRNAs would be helpful to understand the molecular mechanism of AMI and might be useful biomarkers for noninvasive diagnostic application. Further studies are still needed to verify our findings and hypothesis.

Dataset Information

Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

Publications

Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.

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