Human GW182 Paralogs Are the Central Organizers for RNA-Mediated Control of Transcription

Cell Rep. 2017 Aug 15;20(7):1543-1552. doi: 10.1016/j.celrep.2017.07.058.

Abstract

In the cytoplasm, small RNAs can control mammalian translation by regulating the stability of mRNA. In the nucleus, small RNAs can also control transcription and splicing. The mechanisms for RNA-mediated nuclear regulation are not understood and remain controversial, hindering the effective application of nuclear RNAi and investigation of its natural regulatory roles. Here, we reveal that the human GW182 paralogs TNRC6A/B/C are central organizing factors critical to RNA-mediated transcriptional activation. Mass spectrometry of purified nuclear lysates followed by experimental validation demonstrates that TNRC6A interacts with proteins involved in protein degradation, RNAi, the CCR4-NOT complex, the mediator complex, and histone-modifying complexes. Functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation. These findings describe protein complexes capable of bridging RNA-mediated sequence-specific recognition of noncoding RNA transcripts with the regulation of gene transcription.

Keywords: GW182; RNA activation; RNAi; TNRC6A; argonaute; mass spectrometry; nucleus; transcription.

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Autoantigens / genetics*
  • Autoantigens / metabolism
  • Base Sequence
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism
  • Cytoplasm / genetics
  • Cytoplasm / metabolism
  • Gene Silencing
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mediator Complex / genetics*
  • Mediator Complex / metabolism
  • Molecular Sequence Annotation
  • N-Terminal Acetyltransferase E / genetics*
  • N-Terminal Acetyltransferase E / metabolism
  • N-Terminal Acetyltransferases
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • RNA Splicing*
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / metabolism
  • Transcriptional Activation*

Substances

  • Autoantigens
  • CCR4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • MED14 protein, human
  • Mediator Complex
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • RNA-Binding Proteins
  • Receptors, CCR4
  • TNRC6A protein, human
  • WDR5 protein, human
  • Histone-Lysine N-Methyltransferase
  • N-Terminal Acetyltransferase E
  • N-Terminal Acetyltransferases
  • NAT10 protein, human
  • Anaphase-Promoting Complex-Cyclosome