Germ Granules Govern Small RNA Inheritance

In C. elegans nematodes, components of liquid-like germ granules were shown to be required for transgenerational small RNA inheritance. Surprisingly, we show here that mutants with defective germ granules can nevertheless inherit potent small RNA-based silencing responses, but some of the mutants lose this ability after many generations of homozygosity. Animals mutated in pptr-1, which is required for stabilization of P granules in the early embryo, display extraordinarily strong heritable RNAi responses, lasting for tens of generations. Intriguingly, the RNAi capacity of descendants derived from mutants defective in the core germ granule proteins MEG-3 and MEG-4 is determined by the genotype of the ancestors and changes transgenerationally. Further, whether the meg-3/4 mutant alleles were present in the paternal or maternal lineages leads to different transgenerational consequences. Small RNA inheritance, rather than maternal contribution of the germ granules themselves, mediates the transgenerational defects in RNAi of meg-3/4 mutants and their progeny. Accordingly, germ granule defects lead to heritable genome-wide mis-expression of endogenous small RNAs. Upon disruption of germ granules, hrde-1 mutants can inherit RNAi, although HRDE-1 was previously thought to be absolutely required for RNAi inheritance. We propose that germ granules sort and shape the RNA pool, and that small RNA inheritance maintains this activity for multiple generations. [Display omitted] •Disrupting germ granules leads to deviations from Mendelian inheritance•The gene silencing capacity of germ granule mutants changes transgenerationally•Paternal and maternal lineages transmit distinct germ granule-dependent small RNAs•Ancestral germ granules determine the small RNA pools of future generations RNA-rich germ granules are highly conserved and required for germline functions. Lev et al. show that ancestral germ granules shape the gene silencing capacity and small RNA pools of future generations. Altering germ granules in paternal and maternal lineages generates distinct transgenerational dynamics that deviate from Mendelian inheritance.