scholarly journals HERI-1 is a Chromodomain Protein that Negatively Regulates Transgenerational Epigenetic Inheritance

2018 ◽  
Author(s):  
Roberto Perales ◽  
Daniel Pagano ◽  
Gang Wan ◽  
Brandon Fields ◽  
Arneet L. Saltzman ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Epigenetic Inheritance ◽  
Normal Function ◽  
Negative Regulator ◽  
Rnai Pathway ◽  
Transcriptional Gene Silencing ◽  
Direct Role ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Nuclear Rnai

AbstractTransgenerational epigenetic inheritance (TEI) is the inheritance of epigenetic information for two or more generations. In most cases, TEI is limited to 2-3 generations. This short-term nature of TEI could be set by innate biochemical limitations to TEI or by genetically encoded systems that actively limit TEI. dsRNA-mediated gene silencing (RNAi) can be inherited in C. elegans (termed RNAi inheritance or RNA-directed TEI). To identify systems that might actively limit RNA-directed TEI, we conducted a forward genetic screen for factors whose mutation enhanced RNAi inheritance. This screen identified the gene heritable enhancer of RNAi (heri-1), whose mutation causes RNAi inheritance to last longer (>20 generations) than normal. heri-1 encodes a protein with a chromodomain and a kinase-homology domain that is expressed in germ cells and localizes to nuclei. In C. elegans, a nuclear branch of the RNAi pathway (nuclear RNAi or NRDE pathway) is required for RNAi inheritance. We find that this NRDE pathway is hyper-responsive to RNAi in heri-1 mutant animals, suggesting that a normal function of HERI-1 is to limit nuclear RNAi and that limiting nuclear RNAi may be the mechanism by which HERI-1 limits RNAi inheritance. Interestingly, we find that HERI-1 binds to genes targeted by RNAi, suggesting that HERI-1 may have a direct role in limiting nuclear RNAi and, therefore, RNAi inheritance. Surprisingly, recruitment of the negative regulator HERI-1 to genes depends upon that same NRDE factors that drive co-transcriptional gene silencing during RNAi inheritance. We therefore speculate that the generational perdurance of RNAi inheritance is set by competing pro- and anti-silencing outputs of the NRDE nuclear RNAi machinery.

scholarly journals piRNAs Coordinate poly(UG) Tailing to Prevent Aberrant and Permanent Gene Silencing

2021 ◽  
Author(s):  
Aditi Shukla ◽  
Roberto Perales ◽  
Scott Kennedy
Keyword(s):  
Gene Silencing ◽  
Noncoding Rna ◽  
Noncoding Rnas ◽  
Epigenetic Inheritance ◽  
The Self ◽  
Specific Class ◽  
Transgenerational Epigenetic Inheritance ◽  
Small Noncoding Rna ◽  
C Elegans ◽  
Inheritance System

AbstractNoncoding RNAs have emerged as mediators of transgenerational epigenetic inheritance (TEI) in a number of organisms. A robust example of RNA-directed TEI is the inheritance of gene silencing states following RNA interference (RNAi) in the metazoan C. elegans. During RNAi inheritance, gene silencing is transmitted by a self-perpetuating cascade of siRNA-directed poly(UG) tailing of mRNA fragments (pUGylation), followed by siRNA synthesis from poly(UG)-tailed mRNA templates (termed pUG RNA/siRNA cycling). Despite the self-perpetuating nature of pUG RNA/siRNA cycling, RNAi inheritance is finite, suggesting that systems likely exist to prevent permanent RNAi-triggered gene silencing. Here we show that, in the absence of Piwi-interacting RNAs (piRNAs), an animal-specific class of small noncoding RNA, RNAi-based gene silencing can become essentially permanent, lasting at near 100% penetrance for more than five years and hundreds of generations. This permanent gene silencing is mediated by perpetual activation of the pUG RNA/siRNA TEI pathway. Further, we find that piRNAs coordinate endogenous RNAi pathways to prevent germline-expressed genes, which are not normally subjected to TEI, from entering a state of permanent and irreversible epigenetic silencing also mediated by perpetual activation of pUG RNA/siRNA cycling. Together, our results show that one function of C. elegans piRNAs is to insulate germline-expressed genes from aberrant and runaway inactivation by the pUG RNA/siRNA epigenetic inheritance system.

scholarly journals Caenorhabditis elegans nuclear RNAi factor SET-32 deposits the transgenerational histone modification, H3K23me3

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lianna Schwartz-Orbach ◽  
Chenzhen Zhang ◽  
Simone Sidoli ◽  
Richa Amin ◽  
Diljeet Kaur ◽  
...  
Keyword(s):  
Chromatin Modification ◽  
Epigenetic Inheritance ◽  
Rnai Pathway ◽  
C Elegans ◽  
And Function ◽  
Nuclear Rnai ◽  
Factor Set

Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histonemodifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, dsRNA-induced H3K23me3 can persist for multiple generations after the dsRNA exposure has stopped. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

The convergence of autophagy, small RNA and the stress response – implications for transgenerational epigenetic inheritance in plants

2014 ◽  
Vol 5 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Neil A. Youngson ◽  
Pin-Chun Lin ◽  
Shih-Shun Lin
Keyword(s):  
Stress Response ◽  
Viral Infection ◽  
Gene Silencing ◽  
Stress Responses ◽  
Epigenetic Inheritance ◽  
Transcriptional Gene Silencing ◽  
Transgenerational Epigenetic Inheritance ◽  
Protein Levels ◽  
Post Transcriptional Gene Silencing ◽  
Autophagic Degradation

AbstractRecent discoveries in eukaryotes have shown that autophagy-mediated degradation of DICER and ARGONAUTE (AGO), the proteins involved in post-transcriptional gene silencing (PTGS), can occur in response to viral infection and starvation. In plants, a virally encoded protein P0 specifically interacts with AGO1 and enhances degradation through autophagy, resulting in suppression of gene silencing. In HeLa cells, DICER and AGO2 protein levels decreased after nutrient starvation or after treatment to increase autophagy. Environmental exposures to viral infection and starvation have also recently been shown to sometimes not only induce a stress response in the exposed plant but also in their unexposed progeny. These, and other cases of inherited stress response in plants are thought to be facilitated through transgenerational epigenetic inheritance, and the mechanism involves the PTGS and transcriptional gene silencing (TGS) pathways. These recent discoveries suggest that the environmentally-induced autophagic degradation of the PTGS and TGS components may have significant effects on inherited stress responses.

scholarly journals C. elegans nuclear RNAi factor SET-32 deposits the transgenerational heritable histone modification, H3K23me3

2020 ◽  
Author(s):  
Lianna Schwartz-Orbach ◽  
Chenzhen Zhang ◽  
Simone Sidoli ◽  
Richa Amin ◽  
Diljeet Kaur ◽  
...  
Keyword(s):  
Chromatin Modification ◽  
Epigenetic Inheritance ◽  
Rnai Pathway ◽  
C Elegans ◽  
Histone Modifying Enzymes ◽  
And Function ◽  
Nuclear Rnai

AbstractNuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histone modifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, dsRNA-induced H3K23me3 can be inherited for four generations. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

scholarly journals Xrn1p acts at multiple steps in the budding-yeast RNAi pathway to enhance the efficiency of silencing

2020 ◽  
Author(s):  
Matthew A Getz ◽  
David E Weinberg ◽  
Ines A Drinnenberg ◽  
Gerald R Fink ◽  
David P Bartel
Keyword(s):  
Gene Silencing ◽  
Budding Yeast ◽  
Genetic Selection ◽  
Rnai Pathway ◽  
Transcriptional Gene Silencing ◽  
Heterochromatin Formation ◽  
Post Transcriptional Gene Silencing ◽  
Passenger Strand ◽  
Transposon Silencing ◽  
Target Rna

Abstract RNA interference (RNAi) is a gene-silencing pathway that can play roles in viral defense, transposon silencing, heterochromatin formation and post-transcriptional gene silencing. Although absent from Saccharomyces cerevisiae, RNAi is present in other budding-yeast species, including Naumovozyma castellii, which have an unusual Dicer and a conventional Argonaute that are both required for gene silencing. To identify other factors that act in the budding-yeast pathway, we performed an unbiased genetic selection. This selection identified Xrn1p, the cytoplasmic 5′-to-3′ exoribonuclease, as a cofactor of RNAi in budding yeast. Deletion of XRN1 impaired gene silencing in N. castellii, and this impaired silencing was attributable to multiple functions of Xrn1p, including affecting the composition of siRNA species in the cell, influencing the efficiency of siRNA loading into Argonaute, degradation of cleaved passenger strand and degradation of sliced target RNA.

scholarly journals poly(UG)-tailed RNAs in Genome Protection and Epigenetic Inheritance

2019 ◽  
Author(s):  
Aditi Shukla ◽  
Jenny Yan ◽  
Daniel J. Pagano ◽  
Anne E. Dodson ◽  
Yuhan Fei ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Epigenetic Inheritance ◽  
Genome Integrity ◽  
Small Interfering Rnas ◽  
Genetic Elements ◽  
C Elegans ◽  
Transposon Silencing ◽  
Rna Fragments ◽  
Heterologous Expression Systems ◽  
Genome Protection

AbstractMobile genetic elements threaten genome integrity in all organisms. MUT-2/RDE-3 is a ribonucleotidyltransferase required for transposon silencing and RNA interference (RNAi) in C. elegans. When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides to the 3’ termini of these RNAs (polyUG or pUG tails). Here, we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to transposon RNAs, as well as to targets of RNAi. pUG tails with more than 16 perfectly alternating 3’ U and G nucleotides convert otherwise inert RNA fragments into agents of gene silencing. pUG tails promote gene silencing by recruiting RNA-dependent RNA Polymerases (RdRPs), which use pUG-tailed RNAs as templates to synthesize small interfering RNAs (siRNAs). Cycles of pUG RNA-templated siRNA synthesis and siRNA-directed mRNA pUGylation underlie dsRNA-directed transgenerational epigenetic inheritance in the C. elegans germline. Our results show that pUG tails convert RNAs into transgenerational memories of past gene silencing events, which, we speculate, allow parents to inoculate progeny against the expression of unwanted or parasitic genetic elements.

scholarly journals A genome-wide screening for RNAi pathway proteins in Acari

2020 ◽  
Author(s):  
Beatrice T Nganso ◽  
Noa Sela ◽  
Victoria Soroker
Keyword(s):  
Gene Silencing ◽  
Micro Rna ◽  
Rnai Pathway ◽  
Comparative Genomic ◽  
Specific Gene ◽  
C Elegans ◽  
Conserved Sequence ◽  
A Genome ◽  
Systemic Rnai ◽  
Amplification Mechanism

Abstract Background RNA interference (RNAi) is a highly conserved, sequence-specific gene silencing mechanism present in Eukaryotes. Three RNAi pathways critical for organismal development and survival are known, namely micro-RNA (miRNA), Piwi-interacting RNA (piRNA) and short interfering RNA (siRNA) pathways. Little knowledge exist about the genes involved in these pathways in Acari. Moreover, variable successes has been obtained in gene knockdown via siRNA pathway in functional genomics and management of Acari species. We hypothesized that the clue may be in the variability in the composition and the efficacy of siRNAi machinery among Acari. Results Both comparative genomic analyses and domain annotation suggest that all the analyzed species have orthologs of genes that mediate gene silencing via the three RNAi pathways though gene duplication and/or loss have occurred in the different species. We also identified orthologs of Caenorhabditis elegans RNA-dependent RNA polymerase (RdRP) gene in all Acari species though no secondary Argonaute homologs that operate with this gene in siRNA amplification mechanism were found. This finding suggests that the siRNA amplification mechanism present in Acari may be distinct from that described in C. elegans . Moreover, the genomes of these Acari species encode no ortholog of C. elegans systemic RNAi defective 1 (Sid-1) that mediate systemic RNAi, suggesting that the phenomena of systemic and parental RNAi that has been reported in some Acari species probably occur through a different mechanism. Orthologs of RNAi spreading defective-3 (Rsd-3) gene and scavenger receptors namely Eater and SR-CI that mediate endocytosis cellular update of dsRNA in C. elegans and Drosophila melanogaster were found in Acari genomes. This result suggests that cellular dsRNA uptake in Acari is endocytosis-dependent. Detailed phylogenetic analyses of core RNAi pathway genes in the studied Acari species revealed that their evolution is compatible with the proposed monophyletic evolution of this group. Conclusions Taken together, our in silico comparative analyses have revealed the potential activity of all three pathways in Acari. However, much experimental work remains to be done in elucidating the operating mechanisms behind these pathways in particular those that govern systemic/parental RNAi and siRNA amplification in Acari.

scholarly journals The TRIM-NHL protein NHL-2 is a co-factor in the nuclear and somatic RNAi pathways in C. elegans

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gregory M Davis ◽  
Shikui Tu ◽  
Joshua WT Anderson ◽  
Rhys N Colson ◽  
Menachem J Gunzburg ◽  
...  
Keyword(s):  
Small Rna ◽  
Rna Binding ◽  
Meiotic Chromosome ◽  
Rna Stability ◽  
Rnai Pathway ◽  
Regulatory Pathways ◽  
C Elegans ◽  
Bona Fide ◽  
Rna Pathways ◽  
Nuclear Rnai

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 is a bona fide RNA binding protein and, along with RNA-seq data point to a small RNA independent role for NHL-2 in regulating transcripts at the level of RNA stability. Collectively, our data implicate NHL-2 as an essential hub of gene regulatory activity in both the germline and soma.

scholarly journals Xrn1p Acts at Multiple Steps in the Budding-Yeast RNAi Pathway to Enhance the Efficiency of Silencing

2019 ◽  
Author(s):  
Matthew A. Getz ◽  
David E. Weinberg ◽  
Ines A. Drinnenberg ◽  
Gerald R. Fink ◽  
David P. Bartel
Keyword(s):  
Gene Silencing ◽  
Budding Yeast ◽  
Genetic Selection ◽  
Rnai Pathway ◽  
Transcriptional Gene Silencing ◽  
Heterochromatin Formation ◽  
Post Transcriptional Gene Silencing ◽  
Passenger Strand ◽  
Transposon Silencing ◽  
Target Rna

AbstractRNA interference (RNAi) is a gene-silencing pathway that can play roles in viral defense, transposon silencing, heterochromatin formation, and post-transcriptional gene silencing. Although absent from Saccharomyces cerevisiae, RNAi is present in other budding-yeast species, including Naumovozyma castellii, which have an unusual Dicer and a conventional Argonaute that are both required for gene silencing. To identify other factors that act in the budding-yeast pathway, we performed an unbiased genetic selection. This selection identified Xrn1p, the cytoplasmic 5′-to-3′ exoribonuclease, as a cofactor of RNAi in budding yeast. Deletion of XRN1 impaired gene silencing in N. castellii, and this impaired silencing was attributable to multiple functions of Xrn1p, including affecting the composition of siRNA species in the cell, influencing the efficiency of siRNA loading into Argonaute, degradation of cleaved passenger strand, and degradation of sliced target RNA.

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