Argonaute-miRNA Complexes Silence Target mRNAs in the Nucleus of Mammalian Stem Cells

Mol Cell. 2018 Sep 20;71(6):1040-1050.e8. doi: 10.1016/j.molcel.2018.07.020. Epub 2018 Aug 23.


In mammals, gene silencing by the RNA-induced silencing complex (RISC) is a well-understood cytoplasmic posttranscriptional gene regulatory mechanism. Here, we show that embryonic stem cells (ESCs) contain high levels of nuclear AGO proteins and that in ESCs nuclear AGO protein activity allows for the onset of differentiation. In the nucleus, AGO proteins interact with core RISC components, including the TNRC6 proteins and the CCR4-NOT deadenylase complex. In contrast to cytoplasmic miRNA-mediated gene silencing that mainly operates on cis-acting elements in mRNA 3' untranslated (UTR) sequences, in the nucleus AGO binding in the coding sequence and potentially introns also contributed to post-transcriptional gene silencing. Thus, nuclear localization of AGO proteins in specific cell types leads to a previously unappreciated expansion of the miRNA-regulated transcriptome.

Keywords: CCR4-NOT; PAR-CLIP; RISC; RNA binding protein; deadenylation; miRNA.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / physiology*
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Nucleus
  • Cytoplasm
  • Embryonic Stem Cells / metabolism
  • Gene Silencing / physiology*
  • Humans
  • Mammals
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • RNA Interference
  • RNA Stability
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • RNA-Induced Silencing Complex / genetics
  • RNA-Induced Silencing Complex / metabolism
  • Transcription Factors


  • Argonaute Proteins
  • MicroRNAs
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • RNA-Induced Silencing Complex
  • Transcription Factors