Regarding the recent Nature News article (Transcription: Enhancer makes non-coding RNA. Nature 465, 173-174; 2010) about the discovery of enhancer RNAs (eRNAs) and their apparent link with neuronal activity, an initial question that arises is whether these eRNAs are really a new class of small RNAs. The question stems from the striking similarities between eRNAs and microRNAs.

MicroRNAs are a class of regulatory small RNA sequences that inhibit protein translation by first binding specific messenger RNA (mRNA) transcripts at the 3’ untranslated region through sequence complementation, which then targets mRNA for inhibition or degradation by the DICER protein complex. MicroRNAs are short sequences lacking polyadenylation, and are encoded in clusters throughout the genome. In neurons, microRNA expression is often modulated by neuronal activity, which in turn fine-tunes the translation of proteins. The subtle changes in protein translation would have profound effect on synaptic structure and activity, and subsequently memory formation (Nature 439, 283–289; 2006).

Similar to microRNAs, eRNAs described here are short sequences lacking polyadenylation, which are transcribed in response to neuronal activity. The only unique feature of eRNAs is that their transcription occurs at enhancer sites throughout the genome, and relies on activity induced enhancer activation via the CREB binding protein (CBP) pathway.

While the function of eRNAs remains elusive, the Greenberg lab (Harvard, Boston, MA) has come up with a number of possibilities. An attractive hypothesis is that eRNAs may be a distinct class of small RNAs that keeps the chromatin in an opened accessible state favoring transcription. However, a key flaw with this hypothesis is that there is simply no evidence in literature that supports the direct role small RNAs in regulating chromatin structure.

On the contrary, there is ample evidence supporting the role of small RNAs (such as microRNAs) in regulating protein translation. Due to the strong similarities between eRNAs and microRNAs, there remains a more realistic possibility that eRNAs may be simply another class of microRNAs whose expression is controlled by enhancer activity. To that end, it is possible that eRNAs may regulate the expression of the enhancer’s target gene at a translational level, and thus function in a negative feedback loop to regulate protein expression.

With many possibilities in mind, it is clear that further research into the biology of eRNAs is needed before these small RNA molecules can be accurately classified.