MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance

Lev, Itamar; Seroussi, Uri; Gingold, Hila; Bril, Roberta; Anava, Sarit; Rechavi, Oded

doi:10.1016/j.cub.2017.03.008

Cited by 102 publications

(163 citation statements)

References 50 publications

(81 reference statements)

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“…Similarly, exogeneous administration of double strand RNA (dsRNA) triggers exogenous siRNA-mediated transgenerational silencing of cognate genes 5 . Typically, dsRNA-triggered heritable responses persist for 3-5 generations 6,7 , owing to a dedicated pathway which regulates the duration of each heritable response 7,8 . Maintenance of RNAi interference (RNAi) over generations involves specialized argonaute proteins [9][10][11] , amplification of the small RNAs by RNA-dependent RNA Polymerases 12,13 (RdRPs), and chromatin modifiers 8,[14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Lev

Toker

et al. 2019

Preprint

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In C. elegans nematodes, components of liquid-like germ granules were shown to be required for transgenerational small RNA inheritance. Surprisingly, we show here that mutants with defective germ granules (pptr-1, meg-3/4, pgl-1) can nevertheless inherit potent small RNA-based silencing responses, but some of the mutants lose this ability after many generations of homozygosity. Animals mutated in pptr-1, which is required for stabilization of P granules in the early embryo, display extremely strong heritable RNAi responses, which last for tens of generations, long after the responses in wild type animals peter out. The phenotype of mutants defective in the core germ granules proteins MEG-3 and MEG-4, depends on the genotype of the ancestors: Mutants that derive from maternal lineages that had functional MEG-3 and MEG-4 proteins exhibit enhanced RNAi inheritance for multiple generations. While functional ancestral meg-3/4 alleles correct, and even potentiates the ability of mutant descendants to inherit RNAi, defects in germ granules functions can be memorized as well; Wild type descendants that derive from lineages of mutants show impaired RNAi inheritance for many (>16) generations, although their germ granules are intact. Importantly, while P granules are maternally deposited, wild type progeny derived from meg-3/4 male mutants also show reduced RNAi inheritance. Unlike germ granules, small RNAs are inherited also from the sperm.Moreover, we find that the transgenerational effects that depend on the ancestral germ granules require the argonaute protein HRDE-1, which carries heritable small RNAs in the germline. Indeed, small RNA sequencing reveals imbalanced levels of many endogenous small RNAs in germ granules mutants. Strikingly, we find that hrde-1;meg-3/4 triple mutants inherit RNAi, although hrde-1 was previously thought to be essential for heritable silencing. We propose that germ granules sort and shape the RNA pool, and that small RNA inheritance memorizes this activity for multiple generations.

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Section: Introductionmentioning

confidence: 99%

Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Lev

Toker

et al. 2019

Preprint

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“…Knockdown of lpr-5 and dpy-7 triggered increased lethality after methylmercury exposure, supporting epigenetic control of chemical defense mechanisms in the nematode (Rudgalvyte et al, 2017). Increased adulthood resistance to hydrogen peroxide required H3K4 methyltransferase subunits wdr-5.1 and set-2, overlap in mechanism of all three stressors Kishimoto et al, 2017 Genetic Transgenerational H3K9me, small RNA H3K9 mutants progressive decline in fertility, required argonaute factor hdre-1 and H3K9 methyltransferase met-2 Lev et al, 2017 Bisphenol A (BPA) Transgenerational H3K9me3, H3K27me3 Germline transgene desilencing in exposed animals was coupled with decreased H3K9me3 and H3K27me3, as well as reproductive defects and embryonic lethality, for five generations. Repression was rescued by activation of Jumonji demethylases JMJD-2 and JMJD-3/UTX-1.…”

Section: Caenorhabditis Elegans As An Emerging Model System For Envirmentioning

confidence: 83%

Caenorhabditis elegans as an emerging model system in environmental epigenetics

Weinhouse

Truong

Meyer

et al. 2018

Environ and Mol Mutagen

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The roundworm Caenorhabitis elegans has been an established model organism for the study of genetics and developmental biology, including studies of transcriptional regulation, since the 1970s. This model organism has continued to be used as a classical model system as the field of transcriptional regulation has expanded to include scientific advances in epigenetics and chromatin biology. In the last several decades, C. elegans has emerged as a powerful model for environmental toxicology, particularly for the study of chemical genotoxicity. Here, we outline the utility and applicability of C. elegans as a powerful model organism for mechanistic studies of environmental influences on the epigenome. Our goal in this article is to inform the field of environmental epigenetics of the strengths and limitations of the well-established C. elegans model organism as an emerging model for medium-throughput, in vivo exploration of the role of exogenous chemical stimuli in transcriptional regulation, developmental epigenetic reprogramming, and epigenetic memory and inheritance. As the field of environmental epigenetics matures, and research begins to map mechanisms underlying observed associations, new toolkits and model systems, particularly manipulable, scalable in vivo systems that accurately model human transcriptional regulatory circuits, will provide an essential experimental bridge between in vitro biochemical experiments and mammalian model systems. Environ. Mol. Mutagen. 59:560-575, 2018. © 2018 Wiley Periodicals, Inc.

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“…By mutating genes involved in the clock, he could make inheritance of small RNAs and their effects last forever (5,6). …”

Section: Rnas In the Germlinementioning

confidence: 99%

Persistent Epigenetic Memory

Dance¹

2017

BioTechniques

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MET-2-Dependent H3K9 Methylation Suppresses Transgenerational Small RNA Inheritance

Cited by 102 publications

References 50 publications

Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Germ Granules Functions are Memorized by Transgenerationally Inherited Small RNAs

Caenorhabditis elegans as an emerging model system in environmental epigenetics

Persistent Epigenetic Memory

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