Untangling the Role of H3K9 Methylations in Transgenerational Small RNA Inheritance

In C.elegans, disruption of the chromatin landscape produces transgenerational effects, such as inherited increase in lifespan and gradual loss of fertility. Inheritance of histone modifications can be induced by double strand RNA-derived heritable small RNAs. We show that the mortal germline phenotype which is typical to met-2 mutants, defective in H3K9 methylation, depends on HRDE-1, an argonaute that carries small RNAs across generations, and is accompanied by accumulated transgenerational misexpression of heritable small RNAs. We discovered that MET-2 inhibits small RNA inheritance, and as a consequence, induction of RNAi in met-2 mutants leads to permanent RNAi responses that do not terminate even after more than 30 generations. We found that potentiation of heritable RNAi in met-2 animals results from global hyperactivation of the small RNA inheritance machinery. Thus, changes in histone modifications can give rise to drastic transgenerational epigenetic effects, by controlling the overall potency of small RNA inheritance. Overall design: C. elegans worms were grown in 20 degrees and fed either on dsRNA producing bacteria or control empty-vector bearing bacteria. The inheritance of the RNAi response was followed in the subsequent generations which were grown on plates seeded with standard OP-50 bacteria. RNA was extracted from one day adult worms.