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UMD Study Uncovers New Mechanism of Transgenerational RNAi in C. elegans

NEW YORK (GenomeWeb) – While it is known that environmental changes in an organism can trigger changes in its progeny for three or more generations, the exact mechanisms behind such transgenerational epigenetic effects remain unclear.

New research out of the University of Maryland, however, shows that RNAi-inducing double-stranded RNA molecules produced in the neurons of the model organisms Caenorhabditis elegans can be transmitted into the worm's germline, resulting in a gene-silencing effect that can persist for over 25 generations.

The findings demonstrate for the first time that a somatic tissue of an animal can influence a gene's expression over multiple generations by transporting dsRNA to the germline, and point to a previously unknown epigenetic mechanism.

As with most animals, the C. elegans germline is separated from the rest of the body early on in development. And although transgenerational gene silencing can occur when dsRNA is either injected or fed to the worm, these methods deliver the RNAi molecules into the fluid-filled body cavity that surrounds the germline without their entry into the cytosol of any somatic cell.

"Thus, it remains unknown whether somatic cells in C. elegans can export signals for delivery into the germline to cause transgenerational gene silencing," the UMD team wrote in its paper, which appeared in the Proceedings of the National Academy of Sciences.

A number of other groups have shown that gene-regulatory dsRNA known as mobile RNAs can be passed between somatic cells in C. elegans by way of the transmembrane protein SID-1. Because gene silencing by mobile RNAs from neurons appears to be stronger than by ones from other somatic tissues, the UMD scientists looked at whether neurons export mobile RNAs that can enter the germline.

They discovered that this is, indeed, the case. Notably, the scientist also discovered that silencing in the germline was found to be heritable after a single generation of exposure to neuronal mobile RNAs. This stands in contrast to silencing in somatic cells, which requires dsRNA expression in each generation.

The researchers also found that initiation of inherited silencing within the germline requires SID-1, a primary Argonaute RDE-1, a secondary Argonaute HRDE-1, and an RNase D homolog MUT-7. Yet maintenance of inherited silencing is independent of SID-1 and RDE-1, and only requires HRDE-1 and MUT-7.

This transgenerational gene silencing is restricted to the germline, but the UMD team speculates that it could "underlie effects of the environment across generations in some cases.

"For example, expression of some genes within the germline can affect longevity, and transgenerational silencing of such genes might underlie the longevity that results from ancestral starvation in C. elegans," the investigators wrote in PNAS. "Thus, additional experiments are needed to determine the role of mobile RNAs, if any, in the transport of such experience-dependent information from somatic cells to subsequent generations in C. elegans."