scholarly journals POT-1 telomere binding protein promotes a novel form of Transgenerational Epigenetic Inheritance

2019 ◽  
Author(s):  
Evan H. Lister-Shimauchi ◽  
Michael Dinh ◽  
Paul Maddox ◽  
Shawn Ahmed
Keyword(s):  
Small Rnas ◽  
Epigenetic Inheritance ◽  
Future Generations ◽  
Developmental Expression ◽  
Telomeric Dna ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Telomere Binding Protein ◽  
Protection Of Telomeres 1 ◽  
F1 Cross

SummaryTransgenerational Epigenetic Inheritance occurs when gametes transmit forms of information without altering genomic DNA1. Although deficiency for telomerase in human families causes transgenerational shortening of telomeres2, a role for telomeres in Transgenerational Epigenetic Inheritance is unknown. Here we show that Protection Of Telomeres 1 (Pot1) proteins, which interact with single-stranded telomeric DNA3,4, function in gametes to regulate developmental expression of telomeric foci for multiple generations. C. elegans POT-1 and POT-25,6 formed abundant telomeric foci in adult germ cells that vanished in 1-cell embryos and gradually accumulated during development. pot-2 mutants displayed abundant POT-1::mCherry foci throughout development. pot-2 mutant gametes created F1 cross-progeny with constitutively abundant POT-1::mCherry and mNeonGreen::POT-2 foci, which persisted for 6 generations but did not alter telomere length. pot-1 mutant and pot-2; pot-1 double mutant gametes gave rise to progeny with constitutively diminished Pot1 foci. Genomic silencing and small RNAs potentiate many transgenerational effects7 but did not affect Pot1 foci. We conclude that C. elegans POT-1 functions at telomeres of pot-2 mutant gametes to create constitutively high levels of Pot1 foci in future generations. As regulation of telomeres and Pot1 have been tied to cancer8,9, this novel and highly persistent form of Transgenerational Epigenetic Inheritance could be relevant to human health.

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

2019 ◽  
Vol 53 (1) ◽  
pp. 289-311 ◽  
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.

scholarly journals Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Evan H. Lister-Shimauchi ◽  
Michael Dinh ◽  
Paul Maddox ◽  
Shawn Ahmed
Keyword(s):  
Germ Cells ◽  
Binding Proteins ◽  
Epigenetic Inheritance ◽  
Transgenerational Epigenetic Inheritance ◽  
Heterochromatin Formation ◽  
Multiple Generations ◽  
C Elegans ◽  
Protection Of Telomeres 1

AbstractDeficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.

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.

Transgenerational Epigenetic Inheritance

2018 ◽  
Vol 52 (1) ◽  
pp. 21-41 ◽  
Author(s):  
Ana Bošković ◽  
Oliver J. Rando
Keyword(s):  
Genomic Dna ◽  
Epigenetic Inheritance ◽  
Model Systems ◽  
Future Generations ◽  
Molecular Pathways ◽  
Epigenetic Changes ◽  
Transgenerational Epigenetic Inheritance ◽  
Epigenetic Information ◽  
Environmental Perturbations ◽  
Multicellular Organisms

Inheritance of genomic DNA underlies the vast majority of biological inheritance, yet it has been clear for decades that additional epigenetic information can be passed on to future generations. Here, we review major model systems for transgenerational epigenetic inheritance via the germline in multicellular organisms. In addition to surveying examples of epivariation that may arise stochastically or in response to unknown stimuli, we also discuss the induction of heritable epigenetic changes by genetic or environmental perturbations. Mechanistically, we discuss the increasingly well-understood molecular pathways responsible for epigenetic inheritance, with a focus on the unusual features of the germline epigenome.

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 Small RNAs Worm Up Transgenerational Epigenetics Research

DNA ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 37-48
Author(s):  
Alla Grishok
Keyword(s):  
Small Rnas ◽  
Epigenetic Inheritance ◽  
Control Mechanisms ◽  
C Elegans ◽  
Sensory Experiences ◽  
New Findings ◽  
Regulatory Rnas ◽  
Living Organisms ◽  
Flow Of Information ◽  
Self Replication

DNA is central to the propagation and evolution of most living organisms due to the essential process of its self-replication. Yet it also encodes factors that permit epigenetic (not included in DNA sequence) flow of information from parents to their offspring and beyond. The known mechanisms of epigenetic inheritance include chemical modifications of DNA and chromatin, as well as regulatory RNAs. All these factors can modulate gene expression programs in the ensuing generations. The nematode Caenorhabditis elegans is recognized as a pioneer organism in transgenerational epigenetic inheritance research. Recent advances in C. elegans epigenetics include the discoveries of control mechanisms that limit the duration of RNA-based epigenetic inheritance, periodic DNA motifs that counteract epigenetic silencing establishment, new mechanistic insights into epigenetic inheritance carried by sperm, and the tantalizing examples of inheritance of sensory experiences. This review aims to highlight new findings in epigenetics research in C. elegans with the main focus on transgenerational epigenetic phenomena dependent on small RNAs.

scholarly journals Transgenerational Epigenetic Inheritance Factors Localize to Spatially and Temporally Ordered Liquid Droplet Assemblages

2017 ◽  
Author(s):  
Gang Wan ◽  
Brandon D. Fields ◽  
George Spracklin ◽  
Carolyn Phillips ◽  
Scott Kennedy
Keyword(s):  
Rna Binding ◽  
Liquid Droplet ◽  
Epigenetic Inheritance ◽  
Liquid Droplets ◽  
P Granules ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Regulatory Systems ◽  
Processing Pathways ◽  
Non Coding Rnas

AbstractEpigenetic information can be inherited for multiple generations (termed transgenerational epigenetic inheritance or TEI) 1,2. Non-coding RNAs have emerged as important mediators of TEI, although the mechanism(s) by which non-coding RNAs mediate TEI remains poorly understood. dsRNA-mediated gene silencing (RNAi) in C. elegans is a robust example of RNA-directed TEI3–5. To further our understanding of RNA-directed TEI, we conducted a genetic screen in C. elegans to identify genes required for RNAi inheritance. Our screen identified the conserved RNA helicase/Zn finger protein ZNFX-1 and the Argonaute protein WAGO-4. We find that WAGO-4 and ZNFX-1 act cooperatively in inheriting generations to maintain small interfering (si)RNA expression over generational time. ZNFX-1/ WAGO-4 localize to a liquid droplet organelle termed the P granule in early germline blastomeres. Later in development, ZNFX-1/WAGO-4 appear to separate from P granules to form independent foci that are adjacent to, yet remain distinct, from P granules. ZNFX-1/WAGO-4 labeled foci exhibit properties reminiscent of liquid droplets and we name these foci Z granules. In the adult germline, Z granules assemble into ordered tri-droplet assemblages with P granules and another germline droplet-like foci termed the Mutator foci. This work identifies a conserved RNA-binding protein that drives RNA-directed TEI in C. elegans, defines a new germline foci that we term the Z granule, demonstrates that liquid droplet formation is under developmental control, and shows that liquid droplets can assemble into spatially ordered multi-droplet structures. We speculate that temporal and spatial ordering of liquid droplets helps cells organize and coordinate the complex RNA processing pathways underlying gene regulatory systems, such as RNA-directed TEI.

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 Cross-kingdom recognition of bacterial small RNAs induces transgenerational pathogenic avoidance

2019 ◽  
Author(s):  
Rachel Kaletsky ◽  
Rebecca S. Moore ◽  
Lance L. Parsons ◽  
Coleen T. Murphy
Keyword(s):  
Small Rnas ◽  
Pathogenic Bacteria ◽  
Escape Behavior ◽  
Bacterial Species ◽  
Future Generations ◽  
Transgenerational Inheritance ◽  
Signaling System ◽  
Specific Behavior ◽  
C Elegans ◽  
Species Specific

AbstractWe recently discovered that C. elegans can pass on a learned avoidance of pathogenic Pseudomonas aeruginosa (PA14) to four generations of its progeny. This transgenerational inheritance is bacterial species-specific, but how C. elegans recognizes and distinguishes different bacteria and transmits this information to future generations is not apparent. Here we show that small RNAs purified from pathogenic PA14 are sufficient not only to induce avoidance of pathogens in mothers, but also to confer transgenerational inheritance of this species-specific behavior for four generations, all without direct contact with pathogenic bacteria. This behavior requires the small RNA transporters SID-1 and SID-2, RNA interference pathway components, the piRNA Piwi/Argonaute pathway, a functioning germline, and TGF-β ligand daf-7 expression in the ASI sensory neuron. Our results suggest that C. elegans “reads” small RNAs expressed by pathogenic bacteria, and uses this information to induce an escape behavior that lasts for four additional generations. C. elegans may have evolved this trans-kingdom signaling system to avoid pathogens in abundant classes of bacteria in its environment and its microbiome.

scholarly journals A membrane-associated condensate drives paternal epigenetic inheritance in C. elegans

2020 ◽  
Author(s):  
Jan Schreier ◽  
Sabrina Dietz ◽  
Antonio M. de Jesus Domingues ◽  
Ann-Sophie Seistrup ◽  
Dieu An H. Nguyen ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Small Rnas ◽  
Maternal Inheritance ◽  
Epigenetic Inheritance ◽  
C Elegans ◽  
Intrinsically Disordered ◽  
Regulatory Information ◽  
Intrinsically Disordered Region ◽  
Gene Regulatory ◽  
Non Coding Rnas

SUMMARYTransgenerational epigenetic inheritance (TEI) describes the transmission of gene-regulatory information across generations without altering DNA sequences, and allows priming of offspring towards transposable elements (TEs) and changing environmental conditions. One important mechanism that acts in TEI is based on small non-coding RNAs. Whereas factors for maternal inheritance of small RNAs have been identified, paternal inheritance is poorly understood, as much of the cellular content is extruded during spermatogenesis. We identify a phase separation-based mechanism, driven by the protein PEI-1, which is characterized by a BTB-BACK domain and an intrinsically disordered region (IDR). PEI-1 specifically secures the Argonaute protein WAGO-3 within maturing sperm in C. elegans. Localization of PEI granules in mature sperm is coupled, via S-palmitoylation, to myosin-driven transport of membranous organelles. pei-1-like genes are also found in human and often expressed in testis, suggesting that the here identified mechanism may be broadly conserved.

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