Transgenerational Epigenetic Inheritance

Bošković, Ana; Rando, Oliver J.

doi:10.1146/annurev-genet-120417-031404

Cited by 240 publications

(175 citation statements)

References 156 publications

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“…Robust transgenerational inheritance has been observed in a diverse range of organisms, from protozoans and plants through to mammals [1][2][3][4][5][6][7][8][9][10]. These findings imply that a mechanism exists whereby experience-dependent information is transferred between somatic and germline tissues.…”

Section: Introductionmentioning

confidence: 98%

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

O’Brien

Ensbey

Day

et al. 2019

Preprint

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AbstractBackgroundThe traditional concept that heritability occurs exclusively from the transfer of germline-restricted genetics is being challenged by the increasing accumulation of evidence confirming the existence of experience-dependent transgenerational inheritance. However, questions remain unanswered as to how heritable information can be passed from somatic cells. Previous studies have implicated the critical involvement of RNA in heritable transgenerational effects and the high degree of mobility and genomic impact of RNAs in all organisms is an attractive model for the efficient transfer of genetic information.ResultsWe hypothesized that RNA may be transported from a somatic tissue, in this case the brain, of an adult male mouse to the germline, and subsequently to offspring. To investigate this, we injected one hemisphere of the male mouse striatum with an AAV1/9 virus expressing human pre-MIR941 (MIR941). After 2, 8 and 16 weeks following injection, we used an LNA-based qPCR system to detect the presence of virus and human MIR941 in brain, peripheral tissues and offspring, from injected male mice mated with uninjected females. Virus was never detected outside of the brain. Verification of single bands of the correct size for MIR941 was performed using Sanger sequencing while quantitation demonstrated that a small percentage (∼ 1-8%) of MIR941 is transported to the germline and to offspring in about a third of the cases.ConclusionsWe show that somatic RNA can be transported to the germline and passed on to offspring, thereby providing additional evidence of a role for RNA in somatic cell-derived transgenerational effects.

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Section: Introductionmentioning

confidence: 98%

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

O’Brien

Ensbey

Day

et al. 2019

Preprint

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“…Non-coding RNAs, such as PIWI-interacting RNAs (piRNAs) and endogenous small interfering RNAs (endo-siRNAs), contribute to RNA quality control in many eukaryotes and, in some cases, also transmit epigenetic information from parent to progeny 16 . In C. elegans, many instances of transgenerational epigenetic inheritance (TEI) are directed by endo-siRNAs 17 .…”

Section: Introductionmentioning

confidence: 99%

Germ Granules Coordinate RNA-based Epigenetic Inheritance Pathways

Dodson

Kennedy

2019

Preprint

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Germ granules are biomolecular condensates that promote germ cell totipotency in most, if not all, animals. In C. elegans, MEG-3 and MEG-4 are two intrinsically disordered proteins that are redundantly required for the phase separations that drive germ granule assembly in germline blastomeres. Here, we show that animals lacking MEG-3/4 exhibit defects in dsRNA-mediated gene silencing (RNAi) that are due, at least in part, to defects in systemic RNAi. Interestingly, these RNAi defects are transgenerationally disconnected from meg-3/4 genotype: RNAi defects do not arise until 5-9 generations after animals become mutant for meg-3/4, and RNAi defects persist for 9-11 generations after meg-3/4 genotype is restored to wild type. Similar non-Mendelian patterns of inheritance are associated with other mutations that disrupt germ granule formation, indicating that germ granule disruption is the likely cause of genotype/phenotype disconnects. Loss of germ granules is associated with the production of aberrant populations of endogenous siRNAs, which, remarkably, are propagated for ≅10 generations in wild-type descendants of animals that lacked germ granules. sid-1, which encodes a factor required for systemic RNAi in C. elegans, is inappropriately and heritably silenced by aberrantly expressed sid-1 endogenous siRNAs, suggesting that transgenerational silencing of sid-1 likely underlies the heritable defect in RNAi. We conclude that one function of germ granules is to organize RNA-based epigenetic inheritance pathways and that failure to assemble germ granules has consequences that persist across many generations.3

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“…Parental effects fall along a continuum from being instantaneously reversible to nearly irreversible. For example, some mammalian parental effects only take effect during precise gestational periods when embryos are exposed to specific concentrations of maternal hormones (Dloniak, French, & Holekamp, 2006), whereas other parental effects carry over for several generations, even after the environmental cue has been removed (Bošković & Rando, 2018;Cropley, Dang, Martin, & Suter, 2012;Dias & Ressler, 2014). If environmental conditions periodically fluctuate on a timescale that is longer than the breeding cycle, but shorter than reproductive lifetime, then evolution may favour reversible parental effects (Kuijper & Hoyle, 2015).…”

Section: Introductionmentioning

confidence: 99%

Transitions in paternal social status predict patterns of offspring growth and metabolic transcription

et al. 2020

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One type of parental effect occurs when changes in parental phenotype or environment trigger changes to offspring phenotype. Such nongenetic parental effects can be precisely triggered in response to an environmental cue in time‐locked fashion, or in other cases, persist for multiple generations after the cue has been removed, suggesting multiple timescales of action. For parental effects to serve as reliable signals of current environmental conditions, they should be reversible, such that when cues change, offspring phenotypes change in accordance. Social hierarchy is a prevalent feature of the environment, and current parental social status could signal the environment in which offspring will be born. Here, we sought to address parental effects of social status and their timescale of action in mice. We show that territorial competition in seminatural environments affects offspring growth. Although dominant males are not heavier than nondominant or control males, they produce faster growing offspring, particularly sons. The timing, effect‐size, and sex‐specificity of this association are modulated by maternal social experience. We show that a change in paternal social status is sufficient to modulate offspring weight: from one breeding cycle to the next, status‐ascending males produce heavier sons than before, and status‐descending males produce lighter sons than before. Current paternal status is also highly predictive of liver transcription in sons, including molecular pathways controlling oxidative phosphorylation and iron metabolism. These results are consistent with a parental effect of social experience, although alternative explanations are considered. In summary, changes in paternal social status are associated with changes in offspring growth and metabolism.

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Transgenerational Epigenetic Inheritance

Cited by 240 publications

References 156 publications

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

Direct evidence for transport of RNA from the mouse brain to the germline and offspring

Germ Granules Coordinate RNA-based Epigenetic Inheritance Pathways

Transitions in paternal social status predict patterns of offspring growth and metabolic transcription

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