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Mol Cell. 2019 Mar 5. pii: S1097-2765(19)30099-1. doi: 10.1016/j.molcel.2019.02.009. [Epub ahead of print]

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

Author information

1
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
2
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
3
Oncode Institute, Hubrecht Institute-KNAW and University Medical Centre Utrecht, Uppsalalaan 8, 3584 Utrecht, the Netherlands.
4
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. Electronic address: marc.buehler@fmi.ch.

Abstract

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

PMID:
30898439
DOI:
10.1016/j.molcel.2019.02.009
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