Connecting the Dots: Linking Caenorhabditis elegans Small RNA Pathways and Germ Granules

Sundby, Adam E.; Molnar, Ruxandra I.; Claycomb, Julie M.

doi:10.1016/j.tcb.2020.12.012

Cited by 55 publications

(59 citation statements)

References 100 publications

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“…When examining the localization patterns of CSR-1 isoforms, we found that both CSR-1a and CSR-1b are present in at least two types of germ granules that are closely situated on the nuclear periphery: P granules and Z granules (Figure 2B ). Z granules have been implicated in transgenerational epigenetic inheritance, while P granules have been implicated in sRNA biogenesis and exoRNAi ( 78 ). WAGO-4 and the helicase ZNFX-1 were identified as the founding members of Z granules, and only a few other proteins have been identified in association with Z granules so far ( 65 , 76 , 78 , 79 ).…”

Section: Resultsmentioning

confidence: 99%

“…Z granules have been implicated in transgenerational epigenetic inheritance, while P granules have been implicated in sRNA biogenesis and exoRNAi ( 78 ). WAGO-4 and the helicase ZNFX-1 were identified as the founding members of Z granules, and only a few other proteins have been identified in association with Z granules so far ( 65 , 76 , 78 , 79 ). Loss of either wago-4 or znfx-1 did not influence the localization of each other to Z granules ( 65 , 76 ).…”

Section: Resultsmentioning

confidence: 99%

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Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility

Charlesworth

Seroussi

Lehrbach

et al. 2021

Nucleic Acids Research

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The Caenorhabditis elegans genome encodes nineteen functional Argonaute proteins that use 22G-RNAs, 26G-RNAs, miRNAs or piRNAs to regulate target transcripts. Only one Argonaute is essential under normal laboratory conditions: CSR-1. While CSR-1 has been studied widely, nearly all studies have overlooked the fact that the csr-1 locus encodes two isoforms. These isoforms differ by an additional 163 amino acids present in the N-terminus of CSR-1a. Using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG into the long (CSR-1a) and short (CSR-1b) isoforms, we found that CSR-1a is expressed during spermatogenesis and in several somatic tissues, including the intestine. CSR-1b is expressed constitutively in the germline. small RNA sequencing of CSR-1 complexes shows that they interact with partly overlapping sets of 22G-RNAs. Phenotypic analyses reveal that the essential functions of csr-1 described in the literature coincide with CSR-1b, while CSR-1a plays tissue specific functions. During spermatogenesis, CSR-1a integrates into an sRNA regulatory network including ALG-3, ALG-4 and WAGO-10 that is necessary for fertility at 25°C. In the intestine, CSR-1a silences immunity and pathogen-responsive genes, and its loss results in improved survival from the pathogen Pseudomonas aeruginosa. Our findings functionally distinguish the CSR-1 isoforms and highlight the importance of studying each AGO isoform independently.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility

Charlesworth

Seroussi

Lehrbach

et al. 2021

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…In this study, we refer to these condensates collectively as “nuage” following the convention for perinuclear condensates in Drosophila and mammalian systems (Dodson and Kennedy, 2020). Nuage condensates often overlay nucleopores and have been proposed to serve as compartments specialized in transcript surveillance and sRNA amplification (Voronina et al, 2011; Gao and Arkov, 2013; Dodson and Kennedy, 2020; Sundby et al, 2021). What specific functions these compartments play in RNAi inheritance and sRNA amplification is not known.…”

Section: Introductionmentioning

confidence: 99%

Two parallel sRNA amplification cycles contribute to RNAi inheritance in C. elegans

Ouyang

Zhang

Seydoux

2021

Preprint

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RNA-mediated interference (RNAi) is a conserved mechanism that uses small RNAs (sRNAs) to tune gene expression. In C. elegans, exposure to dsRNA induces the production of gene-specific sRNAs that are propagated to progeny not exposed to the dsRNA trigger. We present evidence that RNAi inheritance is mediated by two parallel sRNA amplification loops. The first loop, dependent on the nuclear Argonaute HRDE-1, targets nascent transcripts, and reduces but does not eliminate productive transcription at the locus. The second loop, dependent on the conserved helicase ZNFX-1, targets mature transcripts and concentrates them in perinuclear condensates (nuage). Each amplification loop generates a distinct class of sRNAs, with the ZNFX-1 loop responsible for the bulk of sRNA production on the region targeted by the trigger. By independently targeting nascent and mature transcripts, the HRDE-1 and ZNFX-1 loops ensure maximum silencing in progeny not exposed to the trigger.

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“…C. elegans Argonautes localize to a variety of germ granules (P granules, Mutator foci, Z granules, and SIMR foci) in the germline and early embryo [70]. We carried out Ascaris Argonaute antibody histochemistry on the male and female germlines and early embryo.…”

Section: Localization Of Ascaris Argonautes In Early Embryos and The Germlinementioning

confidence: 99%

Nematode Small RNA Pathways in the Absence of piRNAs

Zagoskin

Wang

Neff

et al. 2021

Preprint

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Small RNA pathways play diverse regulatory roles in the nematode C. elegans. However, our understanding of small RNA pathways, their conservation, and their roles in other nematodes is limited. Here, we analyzed small RNA pathways in the parasitic nematode Ascaris. Ascaris has ten Argonautes with five worm-specific Argonautes (WAGOs) that are associated with secondary 5'-triphosphate small RNAs (22-24G-RNAs). These Ascaris WAGOs and their small RNAs target repetitive sequences (WAGO-1, WAGO-2, WAGO-3, and NRDE-3) or mature mRNAs (CSR-1, NRDE-3, and WAGO-3) and are similar to the C. elegans mutator, nuclear, and CSR-1 small RNA pathways. Ascaris CSR-1 likely functions to "license" gene expression in the absence of an Ascaris piRNA pathway. Ascaris ALG-4 and its associated 26G-RNAs target and appear to repress specific mRNAs during meiosis in the testes. Notably, Ascaris WAGOs (WAGO-3 and NRDE-3) small RNAs change their targets between repetitive sequences and mRNAs during spermatogenesis or in early embryos illustrating target plasticity of these WAGOs. We provide a unique and comprehensive view of mRNA and small RNA expression throughout nematode spermatogenesis that illustrates the dynamics and flexibility of small RNA pathways. Overall, our study provides key insights into the conservation and divergence of nematode small RNA pathways.

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Connecting the Dots: Linking Caenorhabditis elegans Small RNA Pathways and Germ Granules

Cited by 55 publications

References 100 publications

Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility

Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility

Two parallel sRNA amplification cycles contribute to RNAi inheritance in C. elegans

Nematode Small RNA Pathways in the Absence of piRNAs

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