A Cytoplasmic Argonaute Protein Promotes the Inheritance of RNAi

Abstract

Summary: RNAi-elicited gene silencing is heritable and can persist for multiple generations after its initial induction in C. elegans. However, the mechanism by which parental-acquired trait-specific information from RNAi is inherited by the progenies is not fully understood. Here, we identified a cytoplasmic Argonaute protein, WAGO-4, necessary for the inheritance of RNAi. WAGO-4 exhibits asymmetrical translocation to the germline during early embryogenesis, accumulates at the perinuclear foci in the germline, and is required for the inheritance of exogenous RNAi targeting both germline- and soma-expressed genes. WAGO-4 binds to 22G-RNAs and their mRNA targets. Interestingly, WAGO-4-associated endogenous 22G-RNAs target the same cohort of germline genes as CSR-1 and contain untemplated addition of uracil at the 3′ ends. The poly(U) polymerase CDE-1 is required for the untemplated uridylation of 22G-RNAs and inheritance of RNAi. Therefore, we conclude that, in addition to the nuclear RNAi pathway, the cytoplasmic RNAi machinery also promotes RNAi inheritance. : Xu et al. explore the function of a cytoplasmic Argonaute protein WAGO-4 in mediating the multigenerational inheritance of RNAi in C. elegans. This work reports that WAGO-4 binds to 22G-RNAs that target germline-expressed protein-coding genes. A polyU polymerase CDE-1 may promote RNAi inheritance by uridylating WAGO-4-associated 22G-RNAs. Keywords: Nrde, WAGO-4, inheritance, Argonaute, RNAi