Germ granules coordinate RNA-based epigenetic inheritance pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA556040 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9732770.fastq.gz | Fastqsanger.gz | |||
| SRR9732780.fastq.gz | Fastqsanger.gz | |||
| SRR9732790.fastq.gz | Fastqsanger.gz | |||
| SRR9732800.fastq.gz | Fastqsanger.gz | |||
| SRR9732810.fastq.gz | Fastqsanger.gz |
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Project description: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.
2019-08-08 | GSE134683 | GEO
Project description: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 granules 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 lead 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.
2019-07-31 | GSE128112 | GEO
Project description:Germ Granules Govern Small RNA Inheritance
| PRJNA526484 | ENA
Project description: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.
| S-EPMC7316138 | biostudies-literature
Project description:Non-membrane bound organelles such as nucleoli, processing bodies, cajal bodies, and germ granules form via spontaneous self-assembly of specific proteins and RNAs. How these biomolecular condensates form and interact are poorly understood. Here we identify two proteins (ZNFX-1 and WAGO-4) that localize to C. elegans germ granules (P granules) in early germline blastomeres. Later in germline development, ZNFX-1/WAGO-4 separate from P granules to define an independent liquid-like condensate that we term the Z granule. In adult germ cells, Z granules assemble into ordered tri-droplet assemblages with P granules and Mutator foci that we term the PZM granule. Finally, we show that one biological function of ZNFX-1 and WAGO-4 is to interact with RNAs in the C. elegans germline to promote transgenerational epigenetic inheritance (TEI). We speculate that the temporal and spatial ordering of liquid droplet organelles may help cells organize and coordinate the complex RNA processing pathways underlying gene regulatory systems, such as RNA-directed TEI.
2018-03-21 | GSE112109 | GEO
Project description:Germ granules are membrane-less organelles essential for small RNA biogenesis and germline development. Among the conserved properties of germ granules is their association with the nuclear membrane. Recent studies demonstrated that LOTUS domain proteins, EGGD-1 and EGGD-2 (also known as MIP-1 and MIP-2 respectively), promote the formation of perinuclear germ granules in C. elegans. This finding presents a unique opportunity to evaluate the significance of perinuclear localization of germ granules. Here we show that loss of eggd-1 causes the coalescence of germ granules and formation of abnormal cytoplasmic aggregates. Impairment of perinuclear granules affects certain germline classes of small RNAs including Piwi-interacting RNAs. Transcriptome profiling reveals overexpression of spermatogenic and cuticle-related genes in eggd-1 hermaphrodites. We further demonstrate that disruption of germ granules activates HLH-30-mediated transcriptional program in somatic tissues. Collectively, our findings underscore the essential role of EGGD-1 in germ granule organization and reveal an unexpected germ granule-to-soma communication.
2023-07-20 | GSE228858 | GEO
Project description:Germ granules are membrane-less organelles essential for small RNA biogenesis and germline development. Among the conserved properties of germ granules is their association with the nuclear membrane. Recent studies demonstrated that LOTUS domain proteins, EGGD-1 and EGGD-2 (also known as MIP-1 and MIP-2 respectively), promote the formation of perinuclear germ granules in C. elegans. This finding presents a unique opportunity to evaluate the significance of perinuclear localization of germ granules. Here we show that loss of eggd-1 causes the coalescence of germ granules and formation of abnormal cytoplasmic aggregates. Impairment of perinuclear granules affects certain germline classes of small RNAs including Piwi-interacting RNAs. Transcriptome profiling reveals overexpression of spermatogenic and cuticle-related genes in eggd-1 hermaphrodites. We further demonstrate that disruption of germ granules activates HLH-30-mediated transcriptional program in somatic tissues. Collectively, our findings underscore the essential role of EGGD-1 in germ granule organization and reveal an unexpected germ granule-to-soma communication.
2023-07-20 | GSE228857 | GEO
Project description: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.
| S-EPMC6739422 | biostudies-literature
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
Project description:A large resource of epitope-tagged or Cre/CreERT2-expressing mouse models are available for study of germ granules or germline development. The germ granules are proteinaceous, membraneless organelles implicated in germ cell differentiation and maturation; however, their protein and RNA transcript constituents, and their mechanistic insight remain not fully understood. Herein, we generated a versatile germline mouse model through combinatorial tagging of DDX4 for simultaneous expression of three cistronic coding products (C-terminal tagged DDX4 - DDX45HA, EGFP, and CreERT2) under the driving control of endogenous Ddx4 promoter. By leveraging the high-affinity HA tag, we optimized an efficient workflow for purification of germ granules (Chromatoid body, CB) from spermatids, and characterized the landscape of protein constituents and RNA transcripts in CB. Moreover, we explored and ascertained that DDX4-mediated, phase-separation dependent CB integrity is functionally important for recruiting distinctive long RNA transcripts and biogenesis of pachytene- and TE-derived piRNAs. Together, our study generated a versatile germline mouse model with a multiplicity of applications for germline study, and provided mechanistic insight into germline development as dictated by germ granules.
2024-08-05 | GSE273344 | GEO