Intercellular transport of RNA can limit heritable epigenetic changes

Abstract

RNAs in circulation carry sequence-specific regulatory information between cells in animal, plant, and host-pathogen systems. The accumulation of specific RNA species in circulation during human disease states therefore implicates such RNAs in disease-related gene regulation. However, mechanisms of RNA secretion, accumulation and import into cells are not well understood and yet are directly taken advantage of in the delivery of recently approved RNA-based therapeutics. In the tractable animal Caenorhabditis elegans, double-stranded RNA (dsRNA) can be delivered into circulation, accumulate within the germline and reach progeny, raising the potential for intergenerational effects from endogenous RNAs released into parental circulation. Here we provide evidence for spatial, temporal, and substrate specificity in the transport of dsRNA in C. elegans from parental circulation to progeny. Temporary loss of dsRNA transport resulted in the persistent accumulation of mRNA from a germline gene. The expression of this gene varied among siblings and even between gonad arms within one animal. Perturbing RNA regulation of the gene created new epigenetic states that lasted for many generations. Thus, one role for the transport of dsRNA into the C. elegans germline in every generation is to limit heritable changes in gene expression. We speculate that transport of extracellular RNA into germ cells in other systems could similarly buffer against heritable change across generations.