Intergenerational transport of double-stranded RNA limits heritable epigenetic changes

Abstract

RNAs in circulation carry sequence-specific regulatory information between cells in animal, plant, and host-pathogen systems. Double-stranded RNA (dsRNA) delivered into the extracellular space of the nematode C. elegans accumulates within the germline and reaches progeny. Here we provide evidence for spatial, temporal, and substrate specificity in the transport of dsRNA 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 germline in every generation is to limit heritable changes in gene expression.One Sentence SummaryRNA from parental circulation reduces heritable changes in gene expression.

Selecting genes for analysis using historically contingent progress: from RNA changes to protein-protein interactions

“…1 E ). Three more proteins have been proposed to be nucleocapsids encoded from genes within retrotransposons ([4, 7]; Fig. 1 E ).…”

“…Length of boxes near each term in ( B ) indicates log 10 (annotations for GO term in C. elegans ), with largest and smallest bars indicating ~285 and ~8 annotations, and shading indicates -log 10 (Bonferroni-corrected p-value), with black and white indicating a p-value of ~10 −6 and ~10 −1 , respectively. ( C-F ) Network in ( A ) with nodes colored to show number of publications per gene (white, 0; black, ≥100) ( C ), genes that have been the main subject of abstracts on RNA silencing in C. elegans ( D ), pseudogenes (red) ( E ), and genes changed in hrde-1 mutants [10] (red), a sid-1 mutant [4] (blue), or both (orange) ( F ).…”

Evidence for multiple forms of heritable RNA silencing

“…Stable RNA silencing that is maintained for hundreds of generations can be induced by mating wild-type hermaphrodites without mCherry sequences to males with mCherry sequences expressed in the germline either as part of a transgene [4] or fused to the endogenous gene sdg-1 [9]. However, the same mCherry sequence fused to the endogenous gene mex-5 ( mCherry::mex-5 in Fig.…”

Inheritance and maintenance of small RNA‐mediated epigenetic effects

“…[71][72][73][74] The dsRNAs imported in the germline are then transmitted to the embryo, requiring the dsRNA channel protein SID-1 to release dsRNA from vesicles transmitted from germline to embryo. [75,76] In C. elegans, dsRNAs injected in the body cavity of the worm connecting the intestine to the germline colocalize with yolk-containing vesicles. [77] These vesicles originate from the intestine and might also transfer dsRNAs directly to the oocytes.…”

“…Further studies are required to understand the release of the small RNAs from the vesicles, which may also involve a role for RNA transporters, as seen in the case of dsRNA release in the embryos. [75,76]…”