Abstract
Germ granules are biomolecular condensates that promote germ cell totipotency in animals. In C.elegans, MEG-3 and MEG-4 function redundantly to assemble germ granules in germline blastomeres. Here, we show that meg-3/4 mutant animals exhibit defects in RNA interference (RNAi) that are transgenerationally disconnected from the meg-3/4 genotype. Similar non-Mendelian inheritance is associated with other mutations disrupting germ granule formation, indicating that loss of germ granules is the likely cause of the observed disconnects between genotype and phenotype. meg-3/4 animals produce aberrant siRNAs that are propagated for≅10 generations in wild-type descendants of meg-3/4 ancestors. Aberrant siRNAs inappropriately and heritably silence germline-expressed genes including the RNAi gene sid-1, suggesting that transgenerational silencing of sid-1 underlies inherited defects in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that germ granule loss has consequences that persist for many generations.
Highlights
Cells contain many non-membrane-bound organelles that consist of proteins and RNAs that self-assemble via liquid-liquid phase separations (Shin and Brangwynne, 2017)
MEG-3 and MEG-4 are intrinsically disordered proteins that are expressed during early embryogenesis and that function redundantly to nucleate P granule formation in early embryos (Wang et al, 2014; Smith et al, 2016)
P granules may provide this organization, as many endo-siRNA pathway proteins are known to localize to P granules, including the RNase III enzyme Dicer, the Dicer-related factor DRH-3, the endo-siRNA-binding Argonautes Worm-specific Argonautes (WAGOs)-1 and CSR-1, the PIWI-interacting RNAs (piRNAs)-binding Argonaute PRG-1, and the RNA-dependent RNA polymerases (RdRPs) EGO-1 (Claycomb et al, 2009; Batista et al, 2008; Beshore et al, 2011; Gu et al, 2009)
Summary
Deposited small non-coding RNAs direct heritable gene regulation in the C. elegans germline. Dodson and Kennedy provide evidence that biomolecular condensates known as germ granules spatially organize these small RNA-based epigenetic inheritance pathways. Disrupting germ granules triggers changes in small-RNA-based gene regulation that can be inherited across generations.
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