SID-2 Transduces RNAi-Dependent and -Independent Responses to the Environment in Caenorhabditis elegans

Epigenetic mechanisms have been shown to underlie the adaptation of organisms to changing environmental conditions, a process that enhances their and their progeny’s survival. One unique example occurs in the nematode Caenorhabditis elegans, in which dsRNA from the environment can be taken up by the RNA transporter SID-2 to induce systemic and transgenerational silencing of homologous sequences. The environmental RNAi response observed in the laboratory is likely a byproduct of the natural role of sid-2, which remains unknown. Here we investigated ecologically relevant, sid-2-dependent responses to changes in the microbiome. We confirmed prior results showing that worms trained to avoid the pathogen Pseudomonas aeruginosa transmit this behavior to their offspring in a sid-2 dependent manner, likely acting proximal to RNAi pathway activities. We also discovered that changes in microbiome constituents heritably reduced RNAi efficiency and that this change in response to the microbiome shift requires sid-2 as well as the RNA transporter sid-1, a necessary component of the systemic RNAi pathway. Finally, we identified novel sid-2-dependent and microbiome-dependent developmental, behavioral, and physiological phenotypes. These responses are independent of the canonical RNAi pathways but dependent on extracellular vesicle (EV)-associated proteins and factors involved with EV biogenesis and trafficking. Collectively, our results suggest a model wherein SID-2 transduces both RNAi-dependent and RNAi-independent environmental responses.