RNAI timeline
The phenomenon of RNA interference (RNAi) was rst discovered in c.elegans, in which double-stranded RNA (dsRNA) could speci cally silence expression from homologue genes. The rst observation of gene silenc- ing induced by RNA was back in early 1990s in plants. In the efforts to make the color of owers more vivid, researchers created transgenic plants with extra copies of pigment-making gene. To their surprise, instead to
be more colorful, some of the transgenic owers turned out to be white. Production from both the transgenic gene and plants’ endogenous gene had been switched off or “co-suppressed”. The transgenic copy, intended to make more corresponding gene products, surprisingly made less. This phenomenon, namely post transcriptional gene silencing (PTGS), was not limited to plants. Parallel work in c.elegans was carried on in 1995. Guo and Kemphues injected the antisense strand RNAs of certain endogenous gene into worms, with intension that those antisense strands may hybridized to corresponding gene and in turn block translation. Sense strand RNAs, which in fact the same as endogenous target mRNA itself, were used as nega-
tive control. Shockingly, sense strand by itself was found to be as effective
as antisense to suppress gene expression. This mystery was solved in 1998, when Fire and Mello tested the synergy effect of sense and antisense strand together. They found that double-stranded RNA was at least ten-fold or perhaps a hundred fold more potent as a silence trigger than was sense
or antisense alone. Furthermore, they pointed out the repression effect observed by Guo and Kemphues, was in fact caused by trace amount of double-stranded RNA contamination in those samples .
Why does it take so long for people to propose dsRNA as a trigger for the silencing effects observed? First, at the time, dsRNA was thought to be a nonspeci c silencing agent that triggers a global destruction of mRNA and suppression the protein expression in mammalian cells. Second, dsRNA is rather stable and thought to be unavailable for further base pairing to target mRNAs. Any model including dsRNA as a trigger for RNAi is obligated
to involve a whole set of cellular factors to unwind dsRNA and somehow searching the target mRNA sequence in the cellular pool by using a single strand as guide. Although now we know that it is actually how RNAi func- tions, back then, hypothesis comprising of so many unknown activities are rarely appealing. It takes more than brilliant designs of experiments and unarguable scienti c evidences for Fire and Mello to propose dsRNA as the silencing trigger and created the new term –RNAi. And because of that, they were awarded the Noble Prize in 2006.
Citation :
Guo, S. (2015, April 24). Rna timeline. Retrieved May 24, 2016, from http://www.tbiweb.org/tbi/file_dir/TBI2007/TBI2007_2_33.pdf