Biology subjects

Frenk, S.

Publications and source records attributed to Frenk, S..

3 recordsLinked to original sources

bioRxiv2018

DAF-16/Foxo suppresses the transgenerational sterility of prg-1 piRNA mutants via a systemic small RNA pathway

Mutation of the daf-2 insulin/IGF-1 receptor activates the DAF-16/Foxo transcription factor to suppress the transgenerational sterility phenotype of prg-1/piRNA mutants that are deficient for piRNA-mediated genome silencing. As with PRG-1/piRNAs, mutations in the nuclear RNA interference gene nrde-1 compromised germ cell immortality, but deficiency for daf-2 did not suppress the transgenerational sterility of nrde-1 or nrde-4 single mutants or of prg-1; nrde-4 or prg-1; hrde-1 double mutants. NRDE-1 and NRDE-4 promote transcriptional silencing in somatic cells via the nuclear Argonaute protein NRDE-3, which was dispensable for germ cell immortality. However, daf-2 deficiency failed to promote germ cell immortality in prg-1; nrde-3 mutants. Consistently, we found that DAF-16 activity in somatic cells suppressed the transgenerational sterility of prg-1 mutants via the SID-1 dsRNA transmembrane channel that promotes systemic RNAi as well as Dicer, the dsRNA binding protein RDE-4 and the RDRP RRF-3. We conclude that DAF-16 activates a cell-non-autonomous systemic RNAi pathway that promotes small RNA-mediated genome silencing in germ cells to suppress loss of the genomic immune surveillance factor Piwi/PRG-1. Author SummarySmall RNAs can promote genome silencing. The Argonaute protein Piwi interacts with thousands of small RNAs termed piRNAs in germ cells to suppress expression of transposons and foreign genetic elements. However, the Piwi silencing system may be commonly targeted by viral or transposon genomic parasites that seek to suppress the endogenous defences against their expression and replication. Activation of the DAF-16 stress response pathway promotes adult longevity and can also abolish the transgenerational sterility of C. elegans Piwi mutants. We found that DAF-16 accomplishes this by activating a somatic small RNA pathway where small RNAs are initially produced in the soma and are then transported into the germline to suppress expression of a toxic genetic locus in Piwi mutants. Thus, the DAF-16 stress response pathway activates a systemic small RNA cascade to suppress defects in the Piwi/piRNA genome silencing system.

genetics↗

bioRxiv2018

Deficiency for Piwi results in transmission of a heritable stress that promotes longevity via DAF-16/Foxo

The C. elegans Argonaute protein PRG-1/Piwi and associated piRNAs protect metazoan genomes by silencing transposons and other types of foreign DNA. As prg-1 mutants are propagated, their fertility deteriorates prior to the onset of a reproductive arrest phenotype that resembles a starvation-induced stress response. We found that late-generation prg-1 mutants with substantially reduced fertility were long-lived, whereas early- or mid-generation prg-1 mutants had normal lifespans. Loss of the stress response transcription factor DAF-16 caused mid- or late-generation prg-1 mutants to live very short lives, whereas overexpression of DAF-16 enabled both mid- and late-generation prg-1 mutants to live long. Cytoplasmic P-bodies that respond to stress increased in long-lived late-generation prg-1 mutants and were transmitted to F1 but not F2 cross-progeny. Moreover, moderate levels of heritable stress shorten late-generation prg-1 mutant longevity when DAF-16 or P bodies are deficient. Together, these results suggest that the longevity of late-generation prg-1 mutants is a hormetic stress response. However, dauer larvae that occur in response to stress were not observed in late-generation prg-1 mutants. Small germ cell nucleoli that depended on germline DAF-16 were present in late-generation prg-1 mutants but were not necessary for their longevity. We propose that prg-1 mutant germ cells transmit a form of heritable stress, high levels of which promote longevity and strongly reduce fertility. The heritable stress transmitted by PRG-1/Piwi mutant germ cells may be generally relevant to epigenetic inheritance of longevity. Core message of paperprg-1/Piwi mutants with strongly reduced fertility live long and longevity is transmitted for one generation to F1 cross progeny. Stress granules are increased and germ cell nucleoli are small for long-lived Piwi mutants and their F1 progeny. Loss of daf-16 stress response transcription factor or dcap-1 P body protein causes very short life for worms when prg-1 mutant fertility is moderately reduced, whereas moderate fertility is sufficient to extend lifespan when somatic DAF-16 is overexpressed. We propose that prg-1 mutant germ cells transmit a heritable epigenetic factor that is stressful and elicits two hormetic stress responses: reproductive arrest and longevity.

genetics↗

bioRxiv2018

Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase

Small RNAs with homology to telomeres can map to heterochromatic segments of the C. elegans genome, although small RNAs with perfect homology to (TTAGGC)n telomere repeats are exceptionally rare. The heterochromatin mark H3K9me2 is enriched at C. elegans sub-telomeres, and we found that the HP1 protein HPL-2 that binds H3K9me2 promotes telomere stability in the absence of telomerase. Small RNA silencing can promote H3K9 methylation, and we found that telomere stability in the absence of telomerase required WAGO-1 and HRDE-1 Argonaute proteins that bind small RNAs as well as germ granule proteins MUT-7 and MUT-14 that promote small RNA biogenesis. Loss of HRDE-1, WAGO-1 or PPW-2 Argonautes or the germ granule protein MUT-16 resulted in depletion of subtelomeric small RNAs. Loss of telomerase induces biogenesis of subtelomeric small RNAs from 5 end of the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated genome silencing induces TERRA expression, telomere damage and accelerated sterility. We propose that small RNA-mediated heterochromatin formation and telomerase function redundantly to repress a form of telomeric DNA damage that is coupled to TERRA expression and subtelomeric small RNA biogenesis. Long read sequencing revealed few mutations at 5 ends of telomeres for most N2 wild type C. elegans strains. Despite abundant subtelomeric small RNAs, telomere repeats of TERRA strongly resisted RNA-dependent RNA polymerase activity, revealing an exceptional quality of telomere repeat RNA. Article summaryLoss of telomerase and either small RNA biogenesis factors or heterochromatin proteins resulted in rapid onset of telomere fusions. We identified Argonaute proteins that bind to subtelomeric small RNAs and promote telomere stability in the absence of telomerase. Telomeres are transcribed to create the non-coding RNA TERRA that is a composite of subtelomere sequence and telomere repeats. Although subtelomeric small RNAs were upregulated in the absence of telomerase, the telomere sequence of TERRA was completely resistant to small RNA biogenesis. Small RNAs and TERRA may interact to promote repair of damaged telomeres that cannot be healed by telomerase.

genetics↗