Argonaute proteins couple chromatin silencing to alternative splicing

Nat Struct Mol Biol. 2012 Oct;19(10):998-1004. doi: 10.1038/nsmb.2373. Epub 2012 Sep 9.

Abstract

Argonaute proteins play a major part in transcriptional gene silencing in many organisms, but their role in the nucleus of somatic mammalian cells remains elusive. Here, we have immunopurified human Argonaute-1 and Argonaute-2 (AGO1 and AGO2) chromatin-embedded proteins and found them associated with chromatin modifiers and, notably, with splicing factors. Using the CD44 gene as a model, we show that AGO1 and AGO2 facilitate spliceosome recruitment and modulate RNA polymerase II elongation rate, thereby affecting alternative splicing. Proper AGO1 and AGO2 recruitment to CD44 transcribed regions required the endonuclease Dicer and the chromobox protein HP1γ, and resulted in increased histone H3 lysine 9 methylation on variant exons. Our data thus uncover a new model for the regulation of alternative splicing, in which Argonaute proteins couple RNA polymerase II elongation to chromatin modification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism*
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism*
  • Fibroblasts / physiology
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Lysine / metabolism
  • Methylation
  • Mice
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA, Small Interfering
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Spliceosomes / metabolism

Substances

  • AGO1 protein, human
  • AGO2 protein, human
  • Ago2 protein, mouse
  • Argonaute Proteins
  • CBX3 protein, human
  • CD44 protein, human
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Eukaryotic Initiation Factors
  • Histones
  • Hyaluronan Receptors
  • RNA Precursors
  • RNA, Small Interfering
  • Dicer1 protein, mouse
  • Ribonuclease III
  • DEAD-box RNA Helicases
  • Lysine

Associated data

  • GEO/GSE39749