A Family of Argonaute-Interacting Proteins Gates Nuclear RNAi

Mol Cell. 2020 Jun 4;78(5):862-875.e8. doi: 10.1016/j.molcel.2020.04.007. Epub 2020 Apr 28.


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 of NRDE-3 in the early embryo. Additionally, they are negative regulators of nuclear RNAi triggered from exogenous sources. Loss of ENRI-3, an unstable protein expressed mostly in the male germline, misdirects the RNAi response to transposable elements and impairs TEI. The ENRIs determine the potency and specificity of nuclear RNAi responses by gating small RNAs into specific nuclear Argonautes.

Keywords: 22G-RNA; Argonaute; NRDE-3; RNA interference; RNAi; piRNA; trans-generational epigenetic inheritance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Gene Silencing / physiology*
  • Germ Cells / metabolism
  • Nuclear Proteins / metabolism
  • RNA Interference / physiology
  • RNA, Double-Stranded / metabolism
  • RNA, Nuclear / metabolism
  • RNA, Small Interfering / genetics
  • RNA-Binding Proteins / genetics


  • Argonaute Proteins
  • Caenorhabditis elegans Proteins
  • NRDE-3 protein, C elegans
  • Nuclear Proteins
  • RNA, Double-Stranded
  • RNA, Nuclear
  • RNA, Small Interfering
  • RNA-Binding Proteins