On 2014 Sep 15, Samir Ounzain commented:

Very nice editorial discussing the interesting observations recently published from the Yvan Devaux laboratory (Vausort M, Wagner DR, Devaux Y. Long Noncoding RNAs in Patients With Acute Myocardial Infarction. Circ Res. 2014 Sep 12;115(7):668-77. doi:10.1161/CIRCRESAHA.115.303836. Epub 2014 Jul 17. PubMed PMID: 25035150).

The potential for lncRNAs to serve as biomarkers in cardiovascular disease is very exciting and warrants further investigation. In this editorial Skroblin and Mayr raise a couple of very interesting points that need further investigation and discussion.

They state ''All selected lncRNAs have been identified in noncardiac tissues. This lack of cardiac specificity questions their usefulness as predictors of cardiac dysfunction. At best, measuring lncRNA expression in full blood might reflect inflammation at the site of MI''.

We agree strongly with this statement and would like to emphasise that cardiac specific/restricted lncRNAs likely represent the most important candidates both as biomarkers but also as highly specific therapeutic targets for future manipulation. Indeed, we recently demonstrated that through utilising very deep RNA-sequencing coupled with ab initio transcript reconstructions it is possible to identify 1000s of novel heart specific lncRNAs. Importantly we feel sequencing to a high depth, in a very specific context (we sequenced to a depth of 400x106 PE-reads per sample in isolated border zones post myocardial infarction, as compated to 50x106 PE-reads used in most comparable studies)is critical for the idenfication of highly cell/tissue and context specific lncRNAs, that ultimately we believe will represent the most attractive biomarkers and therapeutic targets.

It is worth noting that when utilising this approach, we found that novel previously unknown lncRNAs were both a) much more cardiac specific than mRNAs and annotated lncRNAs (indeed many exhibit cell type specificity within the heart, b) were better correlated with cardiac physiological traits vs cannonical biomarker mRNAs and annotated lncRNAs, supporting the notion novel heart enriched lncRNAs could represent very attractive biomarkers, c) were highly associated with unique heart specific chromatin signatures linked to active -cis control enhancers, again has implications in therapeutic settings as enhancer reprogramming post stress underpins the fetal activation of gene program that is implicated in pathological remodelling and finally d) using a novel approach to infer lncRNA functions based on developmental chromatin state transitions, we found that novel lncRNAs were highly enriched in functional clusters linked to very specific cardiac functional processes including contractility etc.

Many of the novel lncRNAs we identified in this study were conserved in human, and we hope future studies will leverage our data for the identificaiton of novel heart specific biomarkers that may be circulating in the blood. Most studies to date have only assesed the annotated long non-coding transcriptome in this setting, and we believe our paper demonstrates that novel cardiac enriched lncRNAs are likely much more interesting candidates for analysis.

Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.

On 2014 Sep 15, Samir Ounzain commented:

Very nice editorial discussing the interesting observations recently published from the Yvan Devaux laboratory (Vausort M, Wagner DR, Devaux Y. Long Noncoding RNAs in Patients With Acute Myocardial Infarction. Circ Res. 2014 Sep 12;115(7):668-77. doi:10.1161/CIRCRESAHA.115.303836. Epub 2014 Jul 17. PubMed PMID: 25035150).

The potential for lncRNAs to serve as biomarkers in cardiovascular disease is very exciting and warrants further investigation. In this editorial Skroblin and Mayr raise a couple of very interesting points that need further investigation and discussion.

They state ''All selected lncRNAs have been identified in noncardiac tissues. This lack of cardiac specificity questions their usefulness as predictors of cardiac dysfunction. At best, measuring lncRNA expression in full blood might reflect inflammation at the site of MI''.

We agree strongly with this statement and would like to emphasise that cardiac specific/restricted lncRNAs likely represent the most important candidates both as biomarkers but also as highly specific therapeutic targets for future manipulation. Indeed, we recently demonstrated that through utilising very deep RNA-sequencing coupled with ab initio transcript reconstructions it is possible to identify 1000s of novel heart specific lncRNAs. Importantly we feel sequencing to a high depth, in a very specific context (we sequenced to a depth of 400x106 PE-reads per sample in isolated border zones post myocardial infarction, as compated to 50x106 PE-reads used in most comparable studies)is critical for the idenfication of highly cell/tissue and context specific lncRNAs, that ultimately we believe will represent the most attractive biomarkers and therapeutic targets.

It is worth noting that when utilising this approach, we found that novel previously unknown lncRNAs were both a) much more cardiac specific than mRNAs and annotated lncRNAs (indeed many exhibit cell type specificity within the heart, b) were better correlated with cardiac physiological traits vs cannonical biomarker mRNAs and annotated lncRNAs, supporting the notion novel heart enriched lncRNAs could represent very attractive biomarkers, c) were highly associated with unique heart specific chromatin signatures linked to active -cis control enhancers, again has implications in therapeutic settings as enhancer reprogramming post stress underpins the fetal activation of gene program that is implicated in pathological remodelling and finally d) using a novel approach to infer lncRNA functions based on developmental chromatin state transitions, we found that novel lncRNAs were highly enriched in functional clusters linked to very specific cardiac functional processes including contractility etc.

Many of the novel lncRNAs we identified in this study were conserved in human, and we hope future studies will leverage our data for the identificaiton of novel heart specific biomarkers that may be circulating in the blood. Most studies to date have only assesed the annotated long non-coding transcriptome in this setting, and we believe our paper demonstrates that novel cardiac enriched lncRNAs are likely much more interesting candidates for analysis.

Ounzain S, Micheletti R, Beckmann T, Schroen B, Alexanian M, Pezzuto I, Crippa S, Nemir M, Sarre A, Johnson R, Dauvillier J, Burdet F, Ibberson M, Guigó R, Xenarios I, Heymans S, Pedrazzini T. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. Eur Heart J. 2014 Apr 30. [Epub ahead of print] PubMed PMID: 24786300.