A Tunable Mechanism Determines the Transgenerational Duration of Small RNA Inheritance in C.elegans

In C.elegans nematodes small RNAs enable transmission of epigenetic responses across multiple generations. While RNA interference (RNAi) inheritance mechanisms that enable “memorization” of ancestral responses are being elucidated, it is not known why or how, after a few generations, epigenetic effects are “forgotten”. We show that exposure to dsRNA activates a feedback loop that determines the duration of inherited silencing. We find that gene-specific RNAi responses dictate the transgenerational duration of RNAi responses mounted against unrelated genes, elicited separately in previous generations. RNA-seq analysis reveals that aside from silencing of genes with complementary sequences, dsRNA-induced RNAi affects the production of heritable endogenous small RNAs, which regulate the expression of RNAi factors. Manipulating genes in this feedback pathway changes the duration of heritable silencing. Active control of transgenerational effects could be adaptive, since ancestral responses would be detrimental if the environments of the progeny and the ancestors would differ. Overall design: Examination of dsRNA induced transgenerational inheritance in lineages with and without second trigger enhancment Small-RNA sequencing of P0-F3 generations of [1] worms that were exposed to anti-gfp dsRNA at the P0 generation and transferred to control bacteria ("empty vector") at the next generations (F1-F3) [2] worms that were exposed to anti-gfp dsRNA at the P0 generation, transferred to an additional anti-mCherry RNAi plates at the F1 generation ("2nd trigger") and moved to control bacteria at the F2 generations for two generations (F2-F3) and [3] control group of worms that were grown on "empty-vector" plates and were not exposed to RNAi at any stage.