Mobile genetic elements threaten genome integrity in all organisms. MUT-2/RDE-3 is a ribonucleotidyltransferase required for transposon silencing and RNA interference (RNAi) in C. elegans. When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides 5 to the 3' termini of these RNAs (polyUG or pUG tails). Here, we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to transposon RNAs, as well as to targets of RNAi. pUG tails with more than 16 perfectly alternating 3' U and G nucleotides convert otherwise inert RNA fragments into agents of gene silencing. pUG tails promote gene silencing by recruiting RNA-dependent RNA Polymerases (RdRPs), which use pUG-tailed 10 RNAs as templates to synthesize small interfering RNAs (siRNAs). Cycles of pUG RNAtemplated siRNA synthesis and siRNA-directed mRNA pUGylation underlie dsRNAdirected transgenerational epigenetic inheritance in the C. elegans germline. Our resultsshow that pUG tails convert RNAs into transgenerational memories of past gene silencing events, which, we speculate, allow parents to inoculate progeny against the expression of 15 unwanted or parasitic genetic elements..

Heterochromatin exerts a heritable form of eukaryotic gene repression and contributes to chromosome segregation fidelity and genome stability. However, to date there has been no quantitative evaluation of the stability of heterochromatic gene repression. We designed a genetic strategy to capture transient losses of gene silencing in Saccharomyces as permanent, heritable changes in genotype and phenotype. This approach revealed rare transcription within heterochromatin that occurred in approximately 1/1000 cell divisions. In concordance with multiple lines of evidence suggesting these events were rare and transient, single-molecule RNA FISH showed that transcription was limited. The ability to monitor fluctuations in heterochromatic repression uncovered previously unappreciated roles for Sir1, a silencing establishment factor, in the maintenance and/or inheritance of silencing. In addition, we identified the sirtuin Hst3 and its histone target as contributors to the stability of the silenced state. These approaches revealed dynamics of a heterochromatin function that have been heretofore inaccessible.DOI: http://dx.doi.org/10.7554/eLife.05007.001

Epigenetic mechanisms by which cells inherit information are, to a large extent, enabled by DNA methylation and posttranslational modifications of histone proteins. These modifications operate both to influence the structure of chromatin per se and to serve as recognition elements for proteins with motifs dedicated to binding particular modifications. Each of these modifications results from an enzyme that consumes one of several important metabolites during catalysis. Likewise, the removal of these marks often results in the consumption of a different metabolite. Therefore, these so-called epigenetic marks have the capacity to integrate the expression state of chromatin with the metabolic state of the cell. This review focuses on the central roles played by acetyl-CoA, S-adenosyl methionine, NAD+, and a growing list of other acyl-CoA derivatives in epigenetic processes. We also review how metabolites that accumulate as a result of oncogenic mutations are thought to subvert the epigenetic program.