Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Lev, Itamar; Toker, Itai Antoine; Y, Mor; Nitzan, Anat; Weintraub, G.; Bhonkar, Ornit; Shushan, Itay Ben; Seroussi, Uri; Claycomb, Julie M.; Gingold, Hila; Zaidel-Bar, Ronen; Rechavi, Oded

doi:10.1101/576934

Cited by 3 publications

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“…We obtained similar results by administering the double-stranded RNA by injection and by targeting two other maternally expressed genes required for embryogenesis (mex-5 and mex-6) (Figures 2A and S1A). Abnormal RNAi behavior of strains with loss-of-function mutations in meg-3 and meg-4 has also been reported by others (Wan et al, 2018;Lev et al, 2019).…”

Section: Resultssupporting

confidence: 77%

P Granules Protect RNA Interference Genes from Silencing by piRNAs

et al. 2019

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Section: Resultssupporting

confidence: 77%

P Granules Protect RNA Interference Genes from Silencing by piRNAs

et al. 2019

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“…2A and S1A). Abnormal RNAi behavior of strains with loss of function mutations 98 in meg-3 and meg-4 has also been reported by others (Wan et al, 2018;Lev et al, 2019). 99 meg-3 and meg-4 are required maternally for the formation of P granules in embryos (Wang et 100 al., 2014).…”

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confidence: 57%

P granules protect RNA interference genes from silencing by piRNAs

Ouyang

Folkmann

Bernard

et al. 2019

Preprint

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15P granules are perinuclear condensates in C. elegans germ cells proposed to serve as hubs for 16 self/non-self RNA discrimination by Argonautes. We report that a mutant (meg-3 meg-4) that does not 17 assemble P granules in primordial germ cells loses competence for RNA-interference over several 18 generations and accumulates silencing small RNAs against hundreds of endogenous genes, including the 19 RNA-interference genes rde-11 and sid-1. In wild-type, rde-11 and sid-1 transcripts are heavily targeted 20 by piRNAs, accumulate in P granules, but maintain expression. In the primordial germ cells of meg-3 21 meg-4 mutants, rde-11 and sid-1 transcripts disperse in the cytoplasm with the small RNA biogenesis 22 machinery, become hyper-targeted by secondary sRNAs, and are eventually silenced. Silencing requires 23 the PIWI-class Argonaute PRG-1 and the nuclear Argonaute HRDE-1 that maintains trans-generational 24 silencing of piRNA targets. These observations support a "safe harbor" model for P granules in 25 protecting germline transcripts from piRNA-initiated silencing. 26 27In the germ cells of animals, dense RNA-protein condensates accumulate on the cytoplasmic 29 face of the nuclear envelope. These condensates, collectively referred to as nuage, contain components 30 of the small RNA (sRNA) machinery that scan germline transcripts for foreign sequences. For example, in 31Drosophila, components of the piRNA machinery in nuage amplify small RNAs that target transcripts 32 from transposable elements for destruction (Huang et al., 2017). In C. elegans, the PIWI-class Argonaute 33 PRG-1 associates with ~15,000 piRNAs encoded in the genome that scan most, if not all, germline 34 1). Segregation of Argonautes and proteins required for 22G-RNA production into distinct nuage 60 compartments (P granules versus Z granules and mutator foci) could also play a role in sorting 22G-RNAs 61 or limiting their production (Wan et al., 2018). A direct test of these hypotheses, however, has been 62 difficult to obtain as complete loss of P granules causes sterility. 63We previously identified a mutant that affects P granule coalescence only during embryogenesis 64 (Wang et al., 2014). MEG-3 and MEG-4 are intrinsically-disordered proteins present in the germ plasm, a 65 specialized cytoplasm that is partitioned with the germ lineage during early embryonic cleavages (Wang 66 3 and Seydoux, 2013). MEG-3 and MEG-4 form gel-like scaffolds that recruit and stimulate the coalescence 67 of P granule proteins in germ plasm to ensure their partitioning to the embryonic germline and the 68 primordial germ cells Z2 and Z3 (Fig. 1;Putnam et al., 2019). In meg-3 meg-4 embryos, P granules do not 69 coalesce in germ plasm, causing granule components to be partitioned equally to all cells and turned 70 over ( Fig. 1; Wang et al., 2014). Despite lacking P granules during embryogenesis, meg-3 meg-4 71 assemble P granules de novo when the primordial germ cells resume divisions in the first larval stage to 72 generate the ~ 2000 germ cells that constitu...

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Stress Resets Transgenerational Small RNA Inheritance

Houri-Zeevi

Teichman

Gingold

et al. 2019

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Transgenerational inheritance of small RNAs is challenging basic concepts of heredity and achieving control over such responses is of great interest. In C. elegans nematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments and distinguish self from non-self genes. Inheritance of small RNAs is regulated by dedicated machinery and carryover of aberrant heritable small RNA responses was shown to be maladaptive and to induce sterility. Here we show that various types of stress (starvation, high temperatures, and high osmolarity) but not non-stressful changes in cultivation conditions, lead to resetting of small RNA inheritance. We found that stress leads to a genome-wide reduction in heritable small RNA levels and that mutants defective in different stress pathways exhibit irregular RNAi inheritance dynamics. Moreover, we discovered that resetting of heritable RNAi is orchestrated by MAPK pathway factors, the transcription factor SKN-1, and the MET-2 methyltransferase. Termination of small RNA inheritance, and the fact that this process depends on stress, could protect from run-on of environment-

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Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Cited by 3 publications

References 64 publications

P Granules Protect RNA Interference Genes from Silencing by piRNAs

P Granules Protect RNA Interference Genes from Silencing by piRNAs

P granules protect RNA interference genes from silencing by piRNAs

Stress Resets Transgenerational Small RNA Inheritance

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