RNA silencing… or activation? A look on a potential breakthrough in the world of RNAi

The RNA revolution began in 1998 with the discovery that dsRNA could turn off specific genes in roundworms. So far, over 500 miRNA sequences that can be used for interference have been identified in the human genome. But now, it seems that a couple researchers have found a whole new side to the growing world of RNAi.

http://www.nature.com/nature/journal/v448/n7156/full/448855a.html

Dr. Li stumbled upon RNA activation while working on DNA methylation. These chemical tags often silence nearby genes when added to a region of the DNA. Li was attempting to control (and downregulate) the methylation of genes encoding for a tumour-suppressing protein, E-cadherin. He added dsRNA strands complementary to the promoter region of these genes to prostate cancer cell cultures. The promoter sequence enables the expression of the gene it is associated to – in this case, regulates the synthesis of E-Cadherin. What he found was extraordinary: the experiment had actually boosted levels of E-Cadherin in the cell cultures by 4 to 14-fold, thus enhancing the expression of the gene in question.

Growing evidence with other cancer-related genes strengthened the plausibility of this new mechanism. While working with Place, Li found that activation used some of the same key proteins as the silencing pathway, such as Dicer. He was able to fine-tune the level of activation by simply changing the RNA sequence slightly. Finally, Place and Li were able to successfully design miRNA strands that could be used for activation of specific genes such as those for E-Cadherin expression. All this evidence supported the idea that miRNA could use the interference pathway to activate genes.

In the scientific world, the idea of activation has been met with much skepticism. Despite repeated attempts to publish their findings, Place and Li’s paper was only accepted in the Proceedings of the National Academy of Science in August 2006. Without clear knowledge of the mechanism and evidence to support it, their results were considered unconvincing by much of the scientific community. The idea of activation may be struggling because of its fundamental contradiction with the interference dogma.

There have been multiple theories devised to explain the mechanism behind activation. According to some, it may simply be a form of inhibition in disguise, due to the accidental blocking of another silencing RNA or downregulating DNA protein. However, the specificity and predictability of RNA activation through promoter targetting seems to reject that hypothesis. RNA activation also seems to proceed with very different kinetics, taking days to appear but lasting weeks while silencing is usually triggered within hours but ceases after about a week. This reinforces the belief that RNA activation operates directly at the gene-promoter region of the DNA, meaning that the RNA strand would have to sneak into the cell nucleus where DNA is transcribed in order to operate.

While the mechanism of RNA activation and its range of effectiveness are still under investigation, there is no doubt that this new discovery will completely turn around the world of RNA interference and its associated therapeutic applications. One can imagine RNA activation to be used in gene therapy, to upregulate the expression of vital genes in diseased individuals. Enhancing the expression of genes coding for immune cells for treatment of SCID (Severe Combined Immunodeficiency), or of genes coding for tumour-repressing proteins for cancer patients (as done by Li) are two examples of tremendous medical applications that could be brought on by RNA activation.