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

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.

SUBMITTER: Duempelmann L

PROVIDER: S-EPMC6509282 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Duempelmann Lea L Mohn Fabio F Shimada Yukiko Y Oberti Daniele D Andriollo Aude A Lochs Silke S Bühler Marc M

Molecular cell 20190318 3

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 ma ...[more]

PMID: 30898439

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Project description:Phenotypic differences caused by epimutations rather than changes in DNA sequence have been described in various organisms. Epimutations are potentially adaptive if inherited across generations and might even respond to environmental challenges. Yet experimental evidence is scarce1. Examples of heritable phenotypic changes are paramutation in plants and RNA-induced epigenetic silencing (RNAe) in nematodes, in which small RNAs trigger the formation of silent epialleles that are stable across generations2-7. Consequently, RNA-directed epimutagenesis has been associated with persistent gene repression. Here, using the fission yeast Schizosaccharomyces pombe, we demonstrate that RNA-induced epimutations are stably transmitted to subsequent generations also after reactivation of the silenced gene. This enables descendants to remember and reinstate preceding silencing episodes that had occurred in their ancestors. We show that temporary expression of hairpin-derived small interfering RNAs (siRNAs) triggers RNAe that is stably propagated for at least 18 generations upon inactivation of the polymerase-associated factor 1 complex (Paf1C). In the presence of Paf1C, the silent state is lost, but resumes if Paf1C is again impaired, even in the absence of the original trigger and in later generations. Thus, in yeast RNAe installs a molecular imprint that can be inherited through meiosis with no discernible phenotypic consequences. We show that trimethylated histone H3 lysine 9 (H3K9me3) is a major constituent of this imprint, and that stable propagation thereof is coupled to RNA interference (RNAi). Our findings reveal a distinct form of epigenetic memory in which fission yeast cells acquire heritable, transcriptionally active epialleles that confer gene silencing and manifest a phenotype only in particular, recurring situations. This demonstrates that epigenetic inheritance is adaptive and could potentially constitute a strategy to cope with adverse environmental conditions. If conserved in other eukaryotes, this phenomenon will impact our comprehension of natural variation and epigenetics in evolution.

Project description:Ancestral environmental exposures to a variety of environmental toxicants and other factors have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The current study examined the potential transgenerational actions of the herbicide atrazine. Atrazine is one of the most commonly used herbicides in the agricultural industry, in particular with corn and soy crops. Outbred gestating female rats were transiently exposed to a vehicle control or atrazine. The F1 generation offspring were bred to generate the F2 generation and then the F2 generation bred to generate the F3 generation. The F1, F2 and F3 generation control and atrazine lineage rats were aged and various pathologies investigated. The male sperm were collected to investigate DNA methylation differences between the control and atrazine lineage sperm. The F1 generation offspring (directly exposed as a fetus) did not develop disease, but weighed less compared to controls. The F2 generation (grand-offspring) was found to have increased frequency of testis disease and mammary tumors in males and females, early onset puberty in males, and decreased body weight in females compared to controls. The transgenerational F3 generation rats were found to have increased frequency of testis disease, early onset puberty in females, behavioral alterations (motor hyperactivity) and a lean phenotype in males and females. The frequency of multiple diseases was significantly higher in the transgenerational F3 generation atrazine lineage males and females. The transgenerational transmission of disease requires germline (egg or sperm) epigenetic alterations. The sperm differential DNA methylation regions (DMRs), termed epimutations, induced by atrazine were identified in the F1, F2 and F3 generations. Gene associations with the DMRs were identified. For the transgenerational F3 generation sperm, unique sets of DMRs (epimutations) were found to be associated with the lean phenotype or testis disease. These DMRs provide potential biomarkers for transgenerational disease. The etiology of disease appears to be in part due to environmentally induced epigenetic transgenerational inheritance, and epigenetic biomarkers may facilitate the diagnosis of the ancestral exposure and disease susceptibility. Observations indicate that although atrazine does not promote disease in the directly exposed F1 generation, it does have the capacity to promote the epigenetic transgenerational inheritance of disease.

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

Publications

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

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