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Germ granules coordinate RNA-based epigenetic inheritance pathways

ABSTRACT: Germ granules are biomolecular condensates that promote germ cell totipotency in most, if not all, animals. In C. elegans, MEG-3 and MEG-4 are two intrinsically disordered proteins that are redundantly required for the phase separations that drive germ granule assembly in germline blastomeres. Here, we show that animals lacking MEG-3/4 exhibit defects in dsRNA-mediated gene silencing (RNAi) that are due, at least in part, to defects in systemic RNAi. Interestingly, these RNAi defects are transgenerationally disconnected from meg-3/4 genotype: RNAi defects do not arise until 5-9 generations after animals become mutant for meg-3/4, and RNAi defects persist for 9-11 generations after meg-3/4 genotype is restored to wild type. Similar non-Mendelian patterns of inheritance are associated with other mutations that disrupt germ granule formation, indicating that germ granule disruption is the likely cause of genotype/phenotype disconnects. Loss of germ granules is associated with the production of aberrant populations of endogenous siRNAs, which, remarkably, are propagated for ≅10 generations in wild-type descendants of animals that lacked germ granules. sid-1, which encodes a factor required for systemic RNAi in C. elegans, is inappropriately and heritably silenced by aberrantly expressed sid-1 endogenous siRNAs, suggesting that transgenerational silencing of sid-1 likely underlies the heritable defect in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that failure to assemble germ granules has consequences that persist across many generations.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE134683 | GEO | 2019/08/08

REPOSITORIES: GEO

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Germ Granules Govern Small RNA Inheritance

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Recruitment of mRNAs to P granules by gelation with intrinsically-disordered proteins (RNAseq datasets)

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Project description:In animals with germ plasm, specification of the germline involves “germ granules”, cytoplasmic condensates that enrich maternal transcripts in the germline founder cells. In C. elegans embryos, P granules enrich maternal transcripts, but surprisingly P granules are not essential for germ cell fate specification. Here we have described a second condensate in the C. elegans germ plasm. Like canonical P-bodies found in somatic cells, “germline P-bodies” contain regulators of mRNA decapping and deadenylation and, in addition, the intrinsically-disordered proteins MEG-1 and MEG-2 and the TIS11-family RNA-binding protein POS-1. Embryos lacking meg-1 and meg-2 do not stabilize P-body components, miss-regulate POS-1 targets, miss-specify the germline founder cell, and do not develop a germline. Our findings suggest that specification of the germ line involves at least two distinct condensates that independently enrich and regulate maternal mRNAs in the germline founder cells.

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Project description:dsRNA-mediated gene silencing (RNAi) can be inherited for multiple generations in C. elegans. To understand this process we conducted a genetic screen for animals defective for transmitting RNAi silencing signals to future generations. This screen identified the gene heritable RNAi defective (hrde)-1. hrde-1 encodes an Argonaute (Ago) that associates with siRNAs in germ cells of the progeny of animals exposed to dsRNA. In nuclei of these germ cells, HRDE-1 engages the Nrde nuclear RNAi pathway to promote RNAi inheritance, and directs H3K9me3 chromatin marks at RNAi targeted genomic loci. Under normal growth conditions, HRDE-1 associates with endogenously expressed small RNAs, which direct nuclear gene silencing in germ cells. In RNAi inheritance mutant animals, silencing is lost over generational time. Concurrently, RNAi inheritance mutant animals exhibit progressively worsening germline defects that ultimately lead to sterility. These results establish that the Ago HRDE-1 directs gene-silencing events in germ cell nuclei, which are required for multi-generational RNAi inheritance and immortality of the germ cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to ensure immortality of the germ cell lineage.

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A nuclear Argonaute promotes germline immortality and epigenetic inheritance across generations

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P bodies coat germ granules to promote transgenerational gene silencing in C. elegans

Project description:Formation of biomolecular condensates have emerged as a critical mechanism for compartmentation in living cells. Despite interactions between distinct condensates have been reported, the biological relevance of such interactions remains elusive. In germ cells, small RNA silencing factors are enriched in germ granules, which distinct factors are organized into sub-compartments with specific functions linked to genome surveillance or transgenerational gene silencing. Here we showed that perinuclear germ granules are coated by P body, another condensate known for housing untranslated mRNAs and mRNA degradation factors. Disruption of P body factors, including CGH-1/DDX6 and CAR-1/LSM14, lead to dispersal of small RNA factors from perinuclear germ granules and disorganization of sub-compartments within germ granules. We further showed that CAR-1 promote the interactions between CGH-1 with germ granule factors and such interactions are critical for CGH-1’s ability to promote piRNA-mediated gene silencing. Importantly, we observed that cgh-1 mutants are competent in triggering gene silencing but exhibit defects in maintaining gene silencing effects in the subsequent generations. Small RNA sequencing further showed that cgh-1 mutants exhibit defects in amplifying secondary small RNAs, a known carrier of gene silencing memory. Together, our results uncover the function of P body factors in small RNA-mediated transgenerational gene silencing and highlight how the formation and function of one condensate can be regulated by an adjacent, interacting condensate in cells.

2023-06-16 | PXD037342 | Pride

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