Three Rules Explain Transgenerational Small RNA Inheritance in C. elegans

Life experiences trigger transgenerational small RNA-based responses in C. elegans nematodes. Dedicated machinery ensures that heritable effects would re-set, typically after a few generations. Here we show that isogenic individuals differ dramatically in the persistence of transgenerational responses. By examining lineages composed of >20,000 worms we reveal 3 inheritance rules: (1) Once a response is initiated, each isogenic mother stochastically assumes an 9inheritance state9, establishing a commitment that determines the fate of the inheritance. (2) The response that each mother transfers is uniform in each generation of her descendants. (3) The likelihood that an RNAi response would transmit to the progeny increases the more generations the response lasts, according to a 9hot hand9 principle. Mechanistically, the different parental inheritance states correspond to global changes in the expression levels of endogenous small RNAs, immune response genes, and targets of the conserved transcription factor HSF-1. We show that these rules predict the descendants9 developmental rate and resistance to stress.