Faculty Opinions recommendation of Epimutations driven by small RNAs arise frequently but most have limited duration in Caenorhabditis elegans.

AbstractEnvironmental conditions can cause phenotypic changes, part of which can be inherited by subsequent generations via soma-to-germline communication. However, the signaling molecules or pathways that mediate intertissue communication remain unclear. Here, we show that intertissue small RNA communication systems play a key role in the acquisition and inheritance of hormesis effects – stress-induced stress resistance – in Caenorhabditis elegans. The miRNA-processing enzyme DRSH-1 is involved in both the acquisition and the inheritance of hormesis, whereas worm-specific Argonaute (WAGO) proteins, which function with endo-siRNAs, are involved only in its inheritance. Further analyses demonstrate that the miRNA production system in the neuron and the small RNA transport machinery in the intestine are both essential for its acquisition and that both the transport of small RNAs in the germline and the germline Argonaute HRDE-1 complex are required for its inheritance. Our results thus demonstrate that overlapping and distinct roles of small RNA systems in the acquisition and inheritance of hormesis effects.

Download Full-text

The Caenorhabditis elegans TDRD5/7-like protein, LOTR-1, interacts with the helicase ZNFX-1 to balance epigenetic signals in the germline

10.1101/2021.06.18.448978 ◽

2021 ◽

Author(s):

Elisabeth A Marnik ◽

Miguel Vasconcelos Almeida ◽

P Giselle Cipriani ◽

George Chung ◽

Edoardo Caspani ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Small Rna ◽

Small Rnas ◽

Brood Size ◽

Homologous Proteins ◽

P Granules ◽

Transposon Silencing ◽

Tudor Domain ◽

Germ Granules

LOTUS and Tudor domain containing proteins have critical roles in the germline. Proteins that contain these domains, such as Tejas/Tapas in Drosophila, help localize Vasa to the germ granules and facilitate piRNA-mediated transposon silencing. The homologous proteins in mammals, TDRD5 and TDRD7, are required during spermiogenesis. Until now, proteins containing both LOTUS and Tudor domains in Caenorhabditis elegans have remained elusive. Here we describe LOTR-1 (D1081.7), which derives its name from its LOTUS and Tudor domains. Interestingly, LOTR-1 docks next to P granules to colocalize with the broadly conserved Z-granule helicase, ZNFX-1. LOTR-1's Z-granule association requires its Tudor domain, but both LOTUS and Tudor deletions affect brood size when coupled with a knockdown of the Vasa homolog glh-1. In addition to interacting with the germ-granule components WAGO-1, PRG-1 and DEPS-1, we identified a Tudor-dependent association with ZNFX-1. Like znfx-1 mutants, lotr-1 mutants lose small RNAs from the 3' ends of WAGO and Mutator targets, reminiscent of the loss of piRNAs from the 3' ends of piRNA precursor transcripts in mouse Tdrd5 mutants. Our work suggests that LOTR-1 acts in a conserved mechanism that brings small RNA generating mechanisms towards the 3' ends of small RNA templates or precursors.

Download Full-text

Competition between virus-derived and endogenous small RNAs regulates gene expression in Caenorhabditis elegans

Genome Research ◽

10.1101/gr.153296.112 ◽

2013 ◽

Vol 23 (8) ◽

pp. 1258-1270 ◽

Cited By ~ 42

Author(s):

P. Sarkies ◽

A. Ashe ◽

J. Le Pen ◽

M. A. McKie ◽

E. A. Miska

Keyword(s):

Gene Expression ◽

Caenorhabditis Elegans ◽

Small Rnas

Download Full-text

Maternal and zygotic gene regulatory effects of endogenous RNAi pathways

10.1101/453266 ◽

2018 ◽

Cited By ~ 1

Author(s):

Miguel Vasconcelos Almeida ◽

António Miguel de Jesus Domingues ◽

René F. Ketting

Keyword(s):

Gene Expression ◽

Caenorhabditis Elegans ◽

Gene Silencing ◽

Small Rnas ◽

Self Regulation ◽

Fine Tuning ◽

Specific Gene ◽

Next Generation ◽

C Elegans ◽

Argonaute Proteins

AbstractEndogenous small RNAs (sRNAs) and Argonaute proteins are ubiquitous regulators of gene expression in germline and somatic tissues. sRNA-Argonaute complexes are often expressed in gametes and are consequently inherited by the next generation upon fertilization. In Caenorhabditis elegans, 26G-RNAs are primary endogenous sRNAs that trigger the expression of downstream secondary sRNAs. Two subpopulations of 26G-RNAs exist, each of which displaying strongly compartmentalized expression: one is expressed in the spermatogenic gonad and associates with the Argonautes ALG-3/4; plus another expressed in oocytes and in embryos, which associates with the Argonaute ERGO-1. The determinants and dynamics of gene silencing elicited by 26G-RNAs are largely unknown. Here, we provide diverse new insights into these endogenous sRNA pathways of C. elegans. Using genetics and deep sequencing, we dissect a maternal effect of the ERGO-1 branch sRNA pathway. We find that maternal primary sRNAs can trigger the production of zygotic secondary sRNAs that are able to silence targets, even in the absence of zygotic primary triggers. Thus, the interaction of maternal and zygotic sRNA populations, assures target gene silencing throughout animal development. Furthermore, we find that sRNA abundance, the pattern of origin of sRNA and 3’ UTR length are predictors of the regulatory outcome by the Argonautes ALG-3/4. Lastly, we discovered that ALG-3- and ALG-4-bound 26G-RNAs are dampening the expression of their own mRNAs, revealing a negative feedback loop. Altogether, we provide several new regulatory insights on the dynamics, target regulation and self-regulation of the endogenous RNAi pathways of C. elegans.Author SummarySmall RNAs (sRNAs) and their partner Argonaute proteins regulate the expression of target RNAs. When sperm and egg meet upon fertilization, a diverse set of proteins and RNA, including sRNA-Argonaute complexes, is passed on to the developing progeny. Thus, these two players are important to initiate specific gene expression programs in the next generation. The nematode Caenorhabditis elegans expresses several classes of sRNAs. 26G-RNAs are a particular class of sRNAs that are divided into two subpopulations: one expressed in the spermatogenic gonad and another expressed in oocytes and in embryos. In this work, we describe the dynamics whereby oogenic 26G-RNAs setup gene silencing in the next generation. We also show several ways that spermatogenic 26G-RNAs and their partner Argonautes, ALG-3 and ALG-4, use to regulate their targets. Finally, we show that ALG-3 and ALG-4 are fine-tuning their own expression, a rare role of Argonaute proteins. Overall, we provide new insights into how sRNAs and Argonautes are regulating gene expression.

Download Full-text

Translation and codon usage regulate Argonaute slicer activity to trigger small RNA biogenesis

10.1101/2020.09.04.282863 ◽

2020 ◽

Author(s):

Meetali Singh ◽

Eric Cornes ◽

Blaise Li ◽

Piergiuseppe Quarato ◽

Loan Bourdon ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Embryonic Development ◽

Rna Polymerase ◽

Codon Usage ◽

Small Rna ◽

Small Rnas ◽

Rna Dependent Rna Polymerase ◽

Coding Sequences ◽

Germ Granules ◽

Rna Biogenesis

In the Caenorhabditis elegans germline, thousands of mRNAs are concomitantly expressed with antisense 22G-RNAs, which are loaded into the Argonaute CSR-1. Despite their essential functions for animal fertility and embryonic development, how CSR-1 22G-RNAs are produced remains unknown. Here, we show that CSR-1 slicer activity is primarily involved in triggering the synthesis of small RNAs on the coding sequences of germline mRNAs and post-transcriptionally regulates a fraction of targets. CSR-1-cleaved mRNAs prime the RNA-dependent RNA polymerase, EGO-1, to synthesize 22G-RNAs in phase with ribosome translation in the cytoplasm, in contrast to other 22G-RNAs mostly synthesized in germ granules. Moreover, codon optimality and efficient translation antagonize CSR-1 slicing and 22G-RNAs biogenesis. We propose that codon usage differences encoded into mRNA sequences might be a conserved strategy in eukaryotes to regulate small RNA biogenesis and Argonaute targeting.

Download Full-text

Isolation of eight novel Caenorhabditis elegans small RNAs

Gene ◽

10.1016/j.gene.2004.03.004 ◽

2004 ◽

Vol 335 ◽

pp. 47-56 ◽

Cited By ~ 7

Author(s):

M Wachi ◽

T Ogawa ◽

K Yokoyama ◽

Y Hokii ◽

M Shimoyama ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Small Rnas

Download Full-text

H3K9me3 is Required for Inheritance of Small RNAs that Target a Unique Subset of Newly Evolved Genes

10.1101/338582 ◽

2018 ◽

Cited By ~ 5

Author(s):

Itamar Lev ◽

Hila Gingold ◽

Oded Rechavi

Keyword(s):

Rna Interference ◽

Caenorhabditis Elegans ◽

Small Rnas ◽

Foreign Gene ◽

Small Interfering Rnas ◽

Endogenous Gene ◽

C Elegans ◽

Histone 3 ◽

Repressive Chromatin ◽

Genome Wide

AbstractIn Caenorhabditis elegans, RNA interference (RNAi) responses can transmit across generations via small RNAs. RNAi inheritance is associated with Histone-3-Lysine-9 tri-methylation (H3K9me3) of the targeted genes. In other organisms, maintenance of silencing requires a feed-forward loop between H3K9me3 and small RNAs. Here we show that in C. elegans not only is H3K9me3 unnecessary for inheritance, the modification’s function depends on the identity of the RNAi-targeted gene. We found an asymmetry in the requirement for H3K9me3 and the main worm H3K9me3 methyltransferases, SET-25 and SET-32. Both methyltransferases promote heritable silencing of the foreign gene gfp, but are dispensable for silencing of the endogenous gene oma-1. Genome-wide examination of heritable endogenous small interfering RNAs (endo-siRNAs) revealed that the SET-25-dependent heritable endo-siRNAs target newly acquired and highly H3K9me3 marked genes. Thus, “repressive” chromatin marks could be important specifically for heritable silencing of genes which are flagged as “foreign”, such as gfp.

Download Full-text

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

10.1101/292722 ◽

2018 ◽

Author(s):

Charlie Longtine ◽

Stephen Frenk ◽

Shawn Ahmed

Keyword(s):

Dna Damage ◽

Caenorhabditis Elegans ◽

Dna Damage Response ◽

Small Rna ◽

Small Rnas ◽

Argonaute Protein ◽

Heterochromatin Formation ◽

Damage Response ◽

The Stability ◽

Telomere Erosion

AbstractTelomerase deficiency in human somatic cells results in telomere erosion and senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. These phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1. Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres. We propose that small RNA-mediated genome silencing could be broadly relevant to regulation of proliferative aging.

Download Full-text

Multigenerational Regulation of the Caenorhabditis elegans Chromatin Landscape by Germline Small RNAs

Annual Review of Genetics ◽

10.1146/annurev-genet-112618-043505 ◽

2019 ◽

Vol 53 (1) ◽

pp. 289-311 ◽

Cited By ~ 10

Author(s):

Natasha E. Weiser ◽

John K. Kim

Keyword(s):

Gene Expression ◽

Caenorhabditis Elegans ◽

Small Rnas ◽

Model Organism ◽

Epigenetic Inheritance ◽

Small Interfering Rnas ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Small Noncoding Rnas ◽

Rna Pathways

In animals, small noncoding RNAs that are expressed in the germline and transmitted to progeny control gene expression to promote fertility. Germline-expressed small RNAs, including endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs), drive the repression of deleterious transcripts such as transposons, repetitive elements, and pseudogenes. Recent studies have highlighted an important role for small RNAs in transgenerational epigenetic inheritance via regulation of heritable chromatin marks; therefore, small RNAs are thought to convey an epigenetic memory of genomic self and nonself elements. Small RNA pathways are highly conserved in metazoans and have been best described for the model organism Caenorhabditis elegans. In this review, we describe the biogenesis, regulation, and function of C. elegans endo-siRNAs and piRNAs, along with recent insights into how these distinct pathways are integrated to collectively regulate germline gene expression, transgenerational epigenetic inheritance, and ultimately, animal fertility.

Download Full-text