Stress Resets Transgenerational Small RNA Inheritance

Transgenerational inheritance is challenging basic concepts of heredity and achieving control over such responses is of great interest. In C. elegans nematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments. Inheritance of small RNAs is regulated by dedicated machinery and can be tuned by outside cues. Carryover of aberrant heritable small RNA responses was shown to be maladaptive and to induce sterility in certain cases. Here we show that various types of stress (starvation, high temperatures, and hyperosmotic conditions) but not non-stressful changes in cultivation, lead to resetting of small RNA inheritance. We found that stress leads to a genome-wide reduction in heritable small RNA levels and that mutants defective in different stress pathways exhibit irregular RNAi inheritance dynamics. Moreover, we discovered that resetting of heritable RNAi is orchestrated by MAPK pathway factors, the transcription factor SKN-1, and the MET-2 methyltransferase. Termination of small RNA inheritance, and the fact that this process depends on stress, could protect from run-on of environment-irrelevant heritable gene regulation. RNA was extracted from "day one" adult nematodes (strain SX1263) which bears a Pmex-5::GFP transgene, driving GFP expression in the germline. The samples include 3 biological replicates of worms in three stress conditions (heat shock, hyperosmotic conditions, starvation) and a control group, across two generations (F1 and F2), yielding a total of 24 samples.