Inheritance of a Phenotypically Neutral Epimutation Evokes Gene Silencing in Later Generations

Mol Cell. 2019 May 2;74(3):534-541.e4. doi: 10.1016/j.molcel.2019.02.009. Epub 2019 Mar 18.


Small RNAs trigger the formation of epialleles that are silenced across generations. Consequently, RNA-directed epimutagenesis is associated with persistent gene repression. Here, we demonstrate that small interfering RNA-induced epimutations in fission yeast are still inherited even when the silenced gene is reactivated, and descendants can reinstate the silencing phenotype that only occurred in their ancestors. This process is mediated by the deposition of a phenotypically neutral molecular mark composed of tri-methylated histone H3 lysine 9 (H3K9me3). Its stable propagation is coupled to RNAi and requires maximal binding affinity of the Clr4/Suvar39 chromodomain to H3K9me3. In wild-type cells, this mark has no visible impact on transcription but causes gene silencing if RNA polymerase-associated factor 1 complex (Paf1C) activity is impaired. In sum, our results reveal a distinct form of epigenetic memory in which cells acquire heritable, transcriptionally active epialleles that confer gene silencing upon modulation of Paf1C.

Keywords: H3K9me3; Paf1C; RNA interference; RNAe; epigenetic memory; heterochromatin; phenotypic plasticity; si3 mark; transcriptional gene silencing; transgenerational inheritance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Epigenesis, Genetic
  • Gene Silencing*
  • Heterochromatin / genetics*
  • Histone-Lysine N-Methyltransferase
  • Histones / genetics*
  • Methylation
  • Methyltransferases / genetics
  • Mutation / genetics
  • Nuclear Proteins / genetics*
  • RNA Interference
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces pombe Proteins / genetics*


  • Cell Cycle Proteins
  • Heterochromatin
  • Histones
  • Nuclear Proteins
  • Paf1 protein, S pombe
  • Schizosaccharomyces pombe Proteins
  • histone H3 trimethyl Lys4
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • clr4 protein, S pombe