Enhancer RNAs (eRNAs) New Targets for Gene Therapy?

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eRNA transcription drives gene expression. Image by pclermont

Have you heard of gene therapy, anti-oxidant therapy, siRNA therapy, and so on? Well, here is a new kid on that block: Enhancer therapy.

With each breakthrough in Science, scientists come up with new exciting means to control and cure disease, and coin a fancy term to these discoveries. This is the era of ‘enhancer therapy’, as the scientists in University of California and Cambridge would call it.

The transcription of genes is regulated by several cis-regulatory regions, DNA sequences that act as platforms for recruiting and binding of transcription factors like promoters, insulators and enhancers.

Gene enhancers control gene expression at promoters from great distances, even several 100 kilo-base pairs (kb) away, as long as they are not impeded by insulator elements.

A very simplistic way to visualize the action of enhancers is that they act like remotes to ‘turn on’ far away genes, and are aided by mediator proteins to physically link and loop around gene promoters.

Enhancers Transcribe Non-Coding RNA (eRNA)

Until recently, we believed enhancers played passive roles of merely acting as platforms to recruit coactivators to, for initiating transcription. But a recent spate of research makes it abundantly clear that many enhancers also direct the expression of non-coding RNA transcripts, called eRNAs (enhancers RNAs), which, in turn, drive the expression of their cognate genes.

In fact, in response to TLR4 signals in macrophages, enhancer transcription kicks in first, followed by appearance of histone methylation signatures like H3K4me1/H3K4me2/H3K27ac that are necessary for signaling transcription at near-by genes1.

Furthermore, another group of scientists proved that in breast cancer cells, MCF-7, eRNA induction is necessary and predictive of enhancer activity. And they went so far as to prove that, upon stimulation by oestrogen receptor a, eRNA transcription is not merely a by-product of enhancer activation, but is actually crucial to the activation of 17b oestradiol target genes2.

Importantly, Christopher Glass’s group at UC, San Diego has cleverly demonstrated that in mouse macrophages, nuclear receptors Rev-Erbs repress target gene expression by shutting down their corresponding functional eRNAs at enhancers3.

Treating Disease With eRNAs

And as an icing to the cake, just add this new evidence pointing to the association of these large clusters of enhancers spanning 50kb, called ‘super enhancers’ with key genes responsible for cell identity as well as with tumor-associated genes4,5. The authors showed that the effect on gene expression was larger for super-enhancer-associated genes than for those with regular enhancers. This explosion of enhancer research has possibly unearthed a powerful approach to treating diseases by targeted degradation of enhancers and subsequent repression of their target mRNAs.

References

Minna U. Kaikkonen, et allRemodeling of the Enhancer Landscape during Macrophage Activation 
Is Coupled to Enhancer Transcription. (2013). Molecular Cell. Accessed September 1, 2013.

Wenbo Li, et allFunctional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. (2013). Nature: International Weekly Journal of Science. Accessed September 1, 2013.

Michael T.Y. Lam, et all. 2013. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. (2013). Nature: International Weekly Journal of Science.  Accessed September 1, 2013.

Lovén J, et all. Selective inhibition of tumor oncogenes by disruption of super-enhancers. (2013). Cell Press Journal. Accessed September 1, 2013.

Whyte WA, et all. Master transcription factors and mediator establish super-enhancers at key cell identity genes. (2013). Cell Press Journal. Accessed September 1, 2013.

Ren, Bing. Transcription: Enhancers make non coding RNAs. (2010). Nature: International Weekly Journal of Science. Accessed September 1, 2013.

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