Rechavi, O., Minevich, G., & Hobert, O. (2011). Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans Cell, 147 (6), 1248-1256 DOI: 10.1016/j.cell.2011.10.042
A new paper in Cell shows a non-mendelian multigenerational inheritance of an acquired trait in the nematode Caenorhabditis elegans.
It has been known since the 1990s that the induction of RNA interference (RNAi) by the exogenous application of double stranded RNAs leads to specific gene silencing and that in C. elegans these effects are often inherited by the worms progeny. However, the mechanism of this transmission has remained unclear, as have the potential biological roles. This new study uses a series of elegant genetic crosses and a modified viral reporter transgene to clarify these outstanding questions.
The authors used a transgenic worm that supports the autonomous replication of the single strand RNA nodavirus Flock House virus (FHV) modified to express GFP and make it’s replication inducible by heat shock. In the first series of experiments, worms heterozygous for certain components of the RNAi pathway (rde-1 or rde-4) that also contained the heat inducible viral transgene were generated. Upon induction of viral replication a robust antiviral response occurs meaning that no GFP is expressed. When these worms self fertilise to produce a new generation, a quarter of the offspring are homozygotes for the mutant rde1 or rde4. These worms would be expected to be unable to silence viral replication as their RNAi mechanisms are non-functional. Instead they still do not express GFP after heat shock indicating that viral silencing continues. This silencing effect continues for several generations until it gradually ‘wears off’. However this ‘fading’ mode of silencing only occurred in a subset of the worms, in others a more stable inherited silencing occurred where GFP expression never reoccurred after many generations. When these two types of worms were crossed all the offspring had the viral GFP signal eliminated. This showed that the suppression of viral production was transmitted in a non-mendelian fashion, in accord with the silencing factors being diffusible trans-acting factors (rather than a hypothetical genomic locus suppressing virus production that would have segregated in a mendelian manner).
In another series of genetic crosses the authors went on to show that the transgenerational viral silencing was maintained in the absence of the viral template. Finally, the authors isolated viRNAs complementary to regions of the viral genome from worms that must have inherited them from their grandparents.
This new research importantly shows a physiological context for transgenerational transmission of RNA mediated gene silencing, ie in inherited antiviral immunity. It also shows that the mechanism of the transmission of gene silencing can be mediated by inherited small RNA molecules.