A genetic framework for RNAi inheritance in Caenorhabditis elegans

Gene regulation by RNA interference (RNAi) is a conserved process driven by double-stranded RNA (dsRNA). It responds to exogenous cues and drives endogenous gene regulation. In Caenorhabditis elegans, RNAi can be inherited from parents to offspring. While a number of factors have been implicated in this inheritance process, we do not understand how and when they function. Using a new inheritance assay, we establish a hierarchy amongst previously identified inheritance factors. We show that the nuclear Argonaute protein HRDE-1 is required for RNAi establishment in parents and offspring, but not for the inheritance process. In contrast, the cytoplasmic Argonaute protein WAGO-3 is the only factor essential for inheritance, via sperm and oocyte, while not affecting establishment in either parent or offspring. We propose a cycle in which nuclear and cytoplasmic Argonaute proteins interact to generate both a silencing response and a cytoplasmic factor that transmits the silencing between parent and offspring, WAGO-3. Finally, we implicate the RNA helicase ZNFX-1 as a factor that allows the inherited WAGO-3 protein to trigger silencing in the offspring.