March 19, 2019
A distinct form of epigenetic memory
Epigenetic memory of transcriptional gene silencing has been observed in several organisms. However, it was not known whether mechanisms exist that convey transgenerational memory of a silencing “experience”, without silencing the gene permanently. The Bühler group has now found such a phenomenon in a unicellular organism.
The Bühler group has previously shown that synthetic small RNAs can trigger transcriptional silencing of protein-coding genes in fission yeast cells. Because the coding sequence of the silenced gene remains unchanged, and the silent state is inherited to subsequent generations even in the absence of the synthetic small RNAs, this phenomenon can be considered “truly” epigenetic. Importantly, this is only possible if the activity of an RNA polymerase-associated factor (Paf1) is impaired. When that is the case, as the Bühler group has demonstrated, the silent state can be inherited for at least 18 generations. Yet as soon as Paf1 becomes fully functional again, the silenced gene is activated and the silencing phenotype is lost.
“The fact that transgenerational inheritance of RNA-induced transcriptional gene silencing was strictly dependent on Paf1 impairment was a bit disappointing,” says Marc Bühler. “But my PhD student Lea Dümpelmann cheered me up by showing me the results of an experiment which I would never have done myself; I would have thought that it doesn’t make much sense, based on current knowledge.” Essentially, Dümpelmann discovered that cells with fully functional Paf1 “remembered” that a particular gene had been repressed in their ancestors. This memory was passed down to subsequent generations and, remarkably, gene silencing was reinstated by repeated Paf1 impairment. In other words, grandchildren with impaired Paf1 activity showed the gene-silencing phenotype that had been initiated by small RNAs in their grandparents but was temporarily lost in their parents due to fully active Paf1.
In her paper, Dümpelmann dissected the molecular nature of this distinct form of epigenetic memory, demonstrating that it depends on the coupling of RNAi and H3K9 tri-methylation (a well-established “repressive” histone modification). In summary, her results reveal that H3K9 tri-methylation functions as an epigenetic mark that is not repressive per se, and imply that the established role of Paf1 in promoting transcription elongation is particularly important within difficult-to-transcribe chromatin.
“The phenomenon we described is unique in that the phenotypic change only manifests under the same conditions that had enabled acquisition of the epiallele – the impairment of Paf1,” says first author Dümpelmann. “Our results raise the hypothesis that external factors, such as chemicals or metabolites present in the yeast’s immediate environment, could transiently impair Paf1 activity and thereby enable the acquisition of epialleles that repress the production of certain gene products which may be toxic under such conditions. Under normal conditions, such genes would be expressed, but silenced if offspring was challenged by the external factor again. Because this mechanism is stable over generations, it may lead to an increased population fitness under adverse conditions.” This intriguing hypothesis will certainly keep the FMI researchers busy for a while!
Lea Duempelmann, Fabio Mohn, Yukiko Shimada, Daniele Oberti, Aude Andriollo, Silke Lochs, Marc Bühler (2019) Inheritance of a phenotypically neutral epimutation evokes gene silencing in later generations. Molecular Cell, advanced online publication.