A Family of Argonaute-Interacting Proteins Gates Nuclear RNAi

Nuclear RNA interference (RNAi) pathways work together with histone modifications to regulate gene expression and enact an adaptive response to transposable RNA elements. In the germline, nuclear RNAi can lead to trans-generational epigenetic inheritance (TEI) of gene silencing. We identified and characterized a family of nuclear Argonaute-interacting proteins (ENRIs) that control the strength and target specificity of nuclear RNAi in C. elegans, ensuring faithful inheritance of epigenetic memories. ENRI-1/2 prevent misloading of the nuclear Argonaute NRDE-3 with small RNAs that normally effect maternal piRNAs, which prevents precocious nuclear translocation ofNRDE-3 in the earlyembryo. Additionally, they are negative regulators ofnuclearRNAi triggered from exogenous sources. Loss of ENRI-3, an unstable protein expressed mostly in the male germline, misdirects theRNAi response totransposable elements and impairsTEI. TheENRIsdetermine the potencyandspecificity of nuclear RNAi responses by gating small RNAs into specific nuclear Argonautes.