Germ Granules Coordinate RNA-Based Epigenetic Inheritance Pathways

• Published in: Developmental cell Vol. 50; no. 6; pp. 704 - 715.e4
• Main Authors: Dodson, Anne E., Kennedy, Scott
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.09.2019
• Subjects: Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - metabolism; Cytoplasmic Granules - metabolism; endo-siRNA; Epigenesis, Genetic; Gene Expression Regulation; Genotype; Germ Cells - metabolism; germ granules; Inheritance Patterns - genetics; non-coding RNA; non-Mendelian inheritance; phase separation; Phenotype; RNA Interference; RNA, Small Interfering - genetics; Transgenerational epigenetic inheritance; phase separation; non-Mendelian inheritance; non-coding RNA; endo-siRNA; germ granules; Transgenerational epigenetic inheritance
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2019.07.025

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. [Display omitted] •Disrupting germ granules leads to aberrant levels of endogenous small RNAs•Aberrantly expressed small RNAs misregulate germline gene expression•Gene expression defects caused by germ granule loss are inherited across generations Parentally 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.