On 2014 Sep 23, Samir Ounzain commented:

Very nice editorial distilling the main points from our recent study and highlighting some very interesting concepts for future consideration. I would just like to briefly address a couple of the main points.

Hofmann and Boon rightly point out ''it would be interesting to see if exogenous overexpression of one of these transcripts could have increased the mRNA levels of their putative target genes or whether genomic context is the main determininant for enhancer activity of lncRNAs''

This is a fascinating point that we are indeed trying to address,, and one that could have implications for future potential cardiac ''enhancer'' therapies. What we can say is it appears that the majority of enhancer templated lncRNAs, at least their -cis activity is dependant on the nascent endogenously produced transcript recruiting and activating in a ''proximity-transfer'' manner chromatin remodelling complexes. This tends to mean that exogenous over-expression is not sufficient. However examples exist of exogenous over-expression impacting upon endogenous -cis loci. A recent study specifically addressed this issue and provides an excellent experimental framework for how such experiments to test these ideas should be conducted. This group mechanistically characterised an enhancer associated lncRNA named CCAT1-L.

1: Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, Zhang S, Wang HB, Ge J, Lu X, Yang L, Chen LL. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014 Sep;24(9):1150. doi: 10.1038/cr.2014.117. PubMed PMID: 25174407; PubMed Central PMCID: PMC4152739.

Finally Hofmann and Boon ask whether ''enhancer RNAs functionally affects the response to cardiac stress in a disease model like acute myocardial infarction''. This is a major questions ourselves and others in the community are trying to address using various strategies. We do suspect that considering the unique context and tissue specific expression profiles of enhancer associated lncRNAs, they would represent ideal specific therapeutic targets for ''enhancer-therapy'' type approaches post acute cardiac stress. We look forward to see how these concepts will emerge and evolve in the coming years.

Finally it is worth noting that many adult heart specific lncRNAs are also associated with adult heart specific active enhancer sequences. Furthermore, heart specific lncRNAs associated with such enhancers are preferentially modulated post myocardial infarction in the mouse, implicating them in the global enhancer reprogramming that underpins maladaptive cardiac remodelling. More on this can be found ...

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 23, Samir Ounzain commented:

Very nice editorial distilling the main points from our recent study and highlighting some very interesting concepts for future consideration. I would just like to briefly address a couple of the main points.

Hofmann and Boon rightly point out ''it would be interesting to see if exogenous overexpression of one of these transcripts could have increased the mRNA levels of their putative target genes or whether genomic context is the main determininant for enhancer activity of lncRNAs''

This is a fascinating point that we are indeed trying to address,, and one that could have implications for future potential cardiac ''enhancer'' therapies. What we can say is it appears that the majority of enhancer templated lncRNAs, at least their -cis activity is dependant on the nascent endogenously produced transcript recruiting and activating in a ''proximity-transfer'' manner chromatin remodelling complexes. This tends to mean that exogenous over-expression is not sufficient. However examples exist of exogenous over-expression impacting upon endogenous -cis loci. A recent study specifically addressed this issue and provides an excellent experimental framework for how such experiments to test these ideas should be conducted. This group mechanistically characterised an enhancer associated lncRNA named CCAT1-L.

1: Xiang JF, Yin QF, Chen T, Zhang Y, Zhang XO, Wu Z, Zhang S, Wang HB, Ge J, Lu X, Yang L, Chen LL. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 2014 Sep;24(9):1150. doi: 10.1038/cr.2014.117. PubMed PMID: 25174407; PubMed Central PMCID: PMC4152739.

Finally Hofmann and Boon ask whether ''enhancer RNAs functionally affects the response to cardiac stress in a disease model like acute myocardial infarction''. This is a major questions ourselves and others in the community are trying to address using various strategies. We do suspect that considering the unique context and tissue specific expression profiles of enhancer associated lncRNAs, they would represent ideal specific therapeutic targets for ''enhancer-therapy'' type approaches post acute cardiac stress. We look forward to see how these concepts will emerge and evolve in the coming years.

Finally it is worth noting that many adult heart specific lncRNAs are also associated with adult heart specific active enhancer sequences. Furthermore, heart specific lncRNAs associated with such enhancers are preferentially modulated post myocardial infarction in the mouse, implicating them in the global enhancer reprogramming that underpins maladaptive cardiac remodelling. More on this can be found ...

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.