Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint

Gu, Sam Guoping; Pak, Julia; Guang, Shouhong; Maniar, Jay M.; Kennedy, Scott; Fire, Andrew

doi:10.1038/ng.1039

Cited by 248 publications

(299 citation statements)

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“…S1), the mechanisms that are required for transgenerational stability of silencing could be initiated in progeny-potentially during germline development. Thus, the production of secondary small RNAs and deposition of chromatin modifications proposed to be required for transgenerational gene silencing (15,24,29,(39)(40)(41) could be initiated in progeny when parents encounter dsRNA. These considerations also impact the interpretation of experiments evaluating the duration of transgenerational inheritance in response to RNAi (25,42).…”

Section: Discussionmentioning

confidence: 99%

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Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Marre

Traver

Jose

2016

Proc. Natl. Acad. Sci. U.S.A.

106

144

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Experiences during the lifetime of an animal have been proposed to have consequences for subsequent generations. Although it is unclear how such intergenerational transfer of information occurs, RNAs found extracellularly in animals are candidate molecules that can transfer gene-specific regulatory information from one generation to the next because they can enter cells and regulate gene expression. In support of this idea, when double-stranded RNA (dsRNA) is introduced into some animals, the dsRNA can silence genes of matching sequence and the silencing can persist in progeny. Such persistent gene silencing is thought to result from sequencespecific interaction of the RNA within parents to generate chromatin modifications, DNA methylation, and/or secondary RNAs, which are then inherited by progeny. Here, we show that dsRNA can be directly transferred between generations in the worm Caenorhabditis elegans. Intergenerational transfer of dsRNA occurs even in animals that lack any DNA of matching sequence, and dsRNA that reaches progeny can spread between cells to cause gene silencing. Surprisingly, extracellular dsRNA can also reach progeny without entry into the cytosol, presumably within intracellular vesicles. Fluorescently labeled dsRNA is imported from extracellular space into oocytes along with yolk and accumulates in punctate structures within embryos. Subsequent entry into the cytosol of early embryos causes gene silencing in progeny. These results demonstrate the transport of extracellular RNA from one generation to the next to regulate gene expression in an animal and thus suggest a mechanism for the transmission of experience-dependent effects between generations.circulating RNA | parental RNAi | epigenetics | transgenerational inheritance | endocytosis

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Section: Discussionmentioning

confidence: 99%

“…22). Although secondary small RNAs and chromatin marks have been detected in progeny upon parental exposure to dsRNA (23,24), it is unknown where extracellular dsRNA needs to interact with intracellular RNA or DNA to cause gene silencing in progeny.…”

mentioning

confidence: 99%

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Marre

Traver

Jose

2016

Proc. Natl. Acad. Sci. U.S.A.

106

144

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“…In particular, our model does not address the mechanisms by which these marks are transmitted during or after replication, although we have previously shown that straightforward variations of the model can provide the means for epigenetic memory of the mark (20). Other potential mechanisms for epigenetic memory include factors that promote continued recruitment of marking factors to the target site, such as antisense RNA-based targeting of H3K9me3 silencing factors (34,35).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of inherently bounded histone modification domains

Hodges

Crabtree

2012

Proc. Natl. Acad. Sci. U.S.A.

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A central goal of chromatin biology is to reveal how posttranslational histone marks modulate gene expression; however, relatively little is known about the spatial or temporal dynamics of these marks. We previously showed that a dynamic model of histone mark nucleation, propagation, and turnover fits the mean enrichment profiles from 99% of noncentromeric histone H3 lysine 9 trimethylation (H3K9me3) domains in mouse embryonic stem cells without the need for boundary or insulator elements. Here we report the full details of this "inherently bounded" model of histone modification dynamics and describe several dynamic features of the model using H3K9me3 as a paradigm. By analyzing the kinetic and structural constraints that drive formation of inherently bounded domains, we find that such domains are optimized when the rates of marking and turnover are comparable. Additionally, we find that to establish such domains, propagation of the histone marks must occur primarily through local contacts.C hromatin is a dynamic environment subject to spatial and temporal regulation through a number of factors. A central focus of this regulation is the posttranslational modification of histone proteins, whose modification states are associated with a variety of transcription states at a given genetic locus. Unfortunately, there are few quantitative models regarding the dynamics of histone marking and therefore little basis for describing the structure, stability, or fluctuations of histone modification domains.One particular posttranslational histone modification, histone H3 lysine 9 trimethylation (H3K9me3), has served as a paradigm to study how histone marks are propagated in live cells to induce local silencing. In mammalian cells, H3K9me3 is associated with heterochromatic and transcriptionally silent regions (1-4). H3K9me3-based repression requires Heterochromatin Protein 1 (HP1), which mediates cis-spreading of the H3K9me3 mark by binding existing H3K9me3 sites (5-7), oligomerizing to bind neighboring nucleosomes (8, 9), and recruiting H3K9-specific histone methyltransferases (HMTs) (10-13) to induce outward spreading of the mark.Unless opposed, this positive feedback would expand H3K9me3-containing domains without bounds. Several groups have described "insulator elements" in flies, yeast, and other organisms, which prevent further expansion of H3K9me3 marking (14). The presence of these insulator elements gives rise to distinct chromatin boundaries, which suggests chromatin may be packaged into modular, independent structural domains near these elements (15). Additionally, in fission yeast, the matingtype locus is silenced through expansion of H3K9me3 over an ∼20-kbp domain with relatively sharp borders (16, 17). The distinct structure of this histone modification domain, with a large plateau and definite borders, indicates that the expansion of H3K9me3 marks is blocked or subject to increased turnover at the border of the domain, consistent with a boundary element.In mammals, however, such expansive H3K9me3 plateaus in ...

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“…Indeed, in worms which are mutants for the RdRP RRF-1, inherited RNAi diminishes after 2 generations, indicating the RNA amplification is required for long-term transgenerational RNAi effects [21,24]. In addition, it was recently demonstrated that the RRF-1 RdRP is required for effective transgenerational targeting of chromatin [25]. The inherited effect of RNAi on chromatin was shown to be mediated by HRDE-1 (heritable RNAi defective-1, also named WAGO-9; for Worm Specific Argonaute 9) and Nuclear RNAi factors (NRDEs, for Nuclear RNAi Defective).…”

Section: And Text Box)mentioning

confidence: 99%

Guest list or black list: heritable small RNAs as immunogenic memories

Rechavi

2014

Trends in Cell Biology

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Small RNA-mediated gene silencing plays a pivotal role in genome immunity by recognizing and eliminating viruses and transposons which otherwise may colonize the genome. However, this can be challenging since individual genomic parasites are highly diverse, and employ multiple immune evasion techniques. In this review, I discuss a new theory proposing that the integrity of the germline is maintained by transgenerationally-transmitted RNA "memories" that record ancestral gene expression patterns, and delineate "Self" from "Foreign" sequences. To maintain such recollection two tactics are employed in parallel: "black listing" of invading nucleic acids, and "guest listing" of endogenous genes. Studies in a number of organisms have shown that this memorization is used by the next generation small RNAs to act as "Inherited Vaccines" that ambush invading elements, or as "Inherited Licenses" that grant the transcription of autogenous sequences. KeywordsSmall RNA; Transgenerational Inheritance; Inherited Immunity; Self Vs. Non-Self; "Inherited Vaccines" Overview of transgenerational inheritanceEvolution progresses through an interplay between two major forces, selection and variation. Since the formulation of the Modern Synthesis the theory holds that the environment is limited in its contribution to the evolutionary course of action -it affects selection, but not the degree of variation [1,2]. However, recent discoveries in epigenetics suggest that the environment may influence variability as well [1]. If the parental environment is predictive of the conditions that the progeny will face (often for sessile or short-lived organisms), epigenetic responses can change the output of the encoded genetic information in an adaptive manner [3]. For example, the water flea Daphnia changes its normal developmental course and develops a "helmet" that protects it from predators, if it is born to a mother that survived a similar attack [4].Correspondence to: odedrechavi@gmail.com. Over the years, controversy surrounded the study of environmentally affected transgenerational inheritance. Today, an improved understanding of epigenetic mechanisms at the molecular level has provided a logical background to explain how, heretically, an adaptive acquired trait could become heritable [5]. Several epigenetic mechanisms could regulate the expression of relevant genes during transgenerational inheritance including DNA methylation, histone modification, and transmission of regulatory RNAs. Moreover, in many organisms, these pathways appear to be interconnected [5][6][7][8]. Europe PMC Funders GroupThis review will concentrate on recent discoveries that establish a role for small RNAs in transgenerational transmission of acquired defense. Furthermore, exciting examples of RNA-mediated non-Mendelian genetic effects will be discussed, along with their possible implications for the study of evolution and immunology. RNA-mediated gene silencing and inheritanceSince the original discovery that small RNAs derived from exogenously-provided dou...

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Amplification of siRNA in Caenorhabditis elegans generates a transgenerational sequence-targeted histone H3 lysine 9 methylation footprint

Cited by 248 publications

References 70 publications

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Dynamics of inherently bounded histone modification domains

Guest list or black list: heritable small RNAs as immunogenic memories

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