Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans

Abstract

Induced expression of the Flock House virus in the soma of C. elegans results in the RNAi-dependent production of virus-derived, small interfering RNAs (viRNAs), which in turn silence the viral genome. We show here that the viRNA-mediated viral silencing effect is transmitted in a non-Mendelian manner to many ensuing generations. We show that the viral silencing agents, viRNAs, are transgenerationally transmitted in a template-independent manner and work in trans to silence viral genomes present in animals that are deficient in producing their own viRNAs. These results provide evidence for the transgenerational inheritance of an acquired trait, induced by the exposure of animals to a specific, biologically relevant physiological challenge. The ability to inherit such extragenic information may provide adaptive benefits to an animal.

Guest list or black list: heritable small RNAs as immunogenic memories

“…Each nematode produces hundreds of progeny, and therefore small RNAs must be amplified to overcome the transgenerational dilution effect that expands logarithmically. Indeed, in worms which are mutants for the RdRP RRF-1, inherited RNAi diminishes after 2 generations, indicating the RNA amplification is required for long-term transgenerational RNAi effects [21,24]. In addition, it was recently demonstrated that the RRF-1 RdRP is required for effective transgenerational targeting of chromatin [25].…”

“…Small RNAs targeting viral genomes (viRNA) accumulate in wild type infected worms, but not mutant worms [35,36]. Moreover, it was shown that viRNAs are capable of being transmitted between generations of worms [21,24]. RNAi heterozygous mutant worms, which are functionally competent, can generate anti-viral RNAi immunity that protects their homozygous RNAi-mutant progeny from replication of a transgenic Flock House Virus (FHV) for multiple generations [21].…”

“…Moreover, it was shown that viRNAs are capable of being transmitted between generations of worms [21,24]. RNAi heterozygous mutant worms, which are functionally competent, can generate anti-viral RNAi immunity that protects their homozygous RNAi-mutant progeny from replication of a transgenic Flock House Virus (FHV) for multiple generations [21]. Recent experiments suggest that C.elegans worms which are infected with the natural Orsay virus also develop RNAi-based protection which is accumulated over generations, so that the progeny of the infected worms is essentially immuned (Personal communication [37]).…”

“…Recent experiments suggest that C.elegans worms which are infected with the natural Orsay virus also develop RNAi-based protection which is accumulated over generations, so that the progeny of the infected worms is essentially immuned (Personal communication [37]). Thus, an acquired trait, anti-viral immunity, is transferred between generations via a non-Mendelian genetic mechanism, and in direct defiance of Weismann's law [21].…”

“…Stable RNAi-mediated methylation of DNA cannot explain inheritance seen in worms, since in C.elegans cytosine methylation does not seem to occur [20] suggesting alternative RNAi inheritance mechanisms are utilized as well. Indeed, unlike epigenetic effects which are mediated by DNA modifications, heritable RNAi effects were shown to propagate to the next generation of worms as a diffusible epigenetic element (demonstrated using animals in which deletions were introduced to remove the target DNA), suggesting that in C.elegans the chromosomal locus is either redundant or dispensable for transmission of transgenerational memory [16,17,21]. Recent evidence in worms suggests, however, that RNAi inheritance can involve a nuclear RNAi mechanism and chromatin remodeling genes as well [22].…”