Evidence for transgenerational transmission of epigenetic tumor susceptibility in Drosophila.
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ABSTRACT:
SUBMITTER: Xing Y
PROVIDER: S-EPMC1971119 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Epigenetics, or regulation of gene expression independent of DNA sequence, is the missing link between genotype and phenotype. Epigenetic memory, mediated by histone and DNA modifications, is controlled by a set of specialized enzymes, metabolite availability, and signaling pathways. A mostly unstudied subject is how sub-toxic exposure to several xenobiotics during specific developmental stages can alter the epigenome and contribute to the development of disease phenotypes later in life. Furthermore, it has been shown that exposure to low-dose xenobiotics can also result in further epigenetic remodeling in the germ line and contribute to increase disease risk in the next generation (multigenerational and transgenerational effects). We here offer a perspective on current but still incomplete knowledge of xenobiotic-induced epigenetic alterations, and their possible transgenerational transmission. We also propose several molecular mechanisms by which the epigenetic landscape may be altered by environmental xenobiotics and hypothesize how diet and physical activity may counteract epigenetic alterations.
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Project description:Examples of transgenerational transmission of environmentally induced epigenetic traits remain rare and disputed. Abiotic stress can release the transcription of epigenetically suppressed transposons and, noticeably, this activation is only transient. Therefore, it is likely that mechanisms countering the mitotic and meiotic inheritance of stress-triggered chromatin changes must exist but are undefined. To reveal these mechanisms, we screened for Arabidopsis mutants impaired in the resetting of stress-induced loss of epigenetic silencing and found that two chromatin regulators, Decrease in DNA methylation1 (DDM1) and Morpheus' Molecule1 (MOM1), act redundantly to restore prestress state and thus erase "epigenetic stress memory". In ddm1 mutants, stress hyperactivates heterochromatic transcription and transcription persists longer than in the wild type. However, this newly acquired state is not transmitted to the progeny. Strikingly, although stress-induced transcription in mom1 mutants is as rapidly silenced as in wild type, in ddm1 mom1 double mutants, transcriptional signatures of stress are able to persist and are found in the progeny of plants stressed as small seedlings. Our results reveal an important, previously unidentified function of DDM1 and MOM1 in rapid resetting of stress induced epigenetic states, and therefore also in preventing their mitotic propagation and transgenerational inheritance.
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Project description:Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT-susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner.
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Project description:Evidence is now emerging that early life environment can have lifelong effects on metabolic, cardiovascular, and pulmonary function in offspring, a concept also known as fetal or developmental programming. In mammals, developmental programming is thought to occur mainly via epigenetic mechanisms, which include DNA methylation, histone modifications, and expression of non-coding RNAs. The effects of developmental programming can be induced by the intrauterine environment, leading to intergenerational epigenetic effects from one generation to the next. Transgenerational epigenetic inheritance may be considered when developmental programming is transmitted across generations that were not exposed to the initial environment which triggered the change. So far, inter- and transgenerational programming has been mainly described for cardiovascular and metabolic disease risk. In this review, we discuss available evidence that epigenetic inheritance also occurs in respiratory diseases, using asthma and chronic obstructive pulmonary disease (COPD) as examples. While multiple epidemiological as well as animal studies demonstrate effects of 'toxic' intrauterine exposure on various asthma-related phenotypes in the offspring, only few studies link epigenetic marks to the observed phenotypes. As epigenetic marks may distinguish individuals most at risk of later disease at early age, it will enable early intervention strategies to reduce such risks. To achieve this goal further, well designed experimental and human studies are needed.
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Project description:Plants grown in spaceflight exhibited differential methylation responses and this is important because plants are sessile, they are constantly exposed to a variety of environmental pressures and respond to them in many ways. We previously showed that the Arabidopsis genome exhibited lower methylation level after spaceflight for 60 h in orbit. Here, using the offspring of the seedlings grown in microgravity environment in the SJ-10 satellite for 11 days and returned to Earth, we systematically studied the potential effects of spaceflight on DNA methylation, transcriptome, and phenotype in the offspring. Whole-genome methylation analysis in the first generation of offspring (F1) showed that, although there was no significant difference in methylation level as had previously been observed in the parent plants, some residual imprints of DNA methylation differences were detected. Combined DNA methylation and RNA-sequencing analysis indicated that expression of many pathways, such as the abscisic acid-activated pathway, protein phosphorylation, and nitrate signaling pathway, etc. were enriched in the F1 population. As some phenotypic differences still existed in the F2 generation, it was suggested that these epigenetic DNA methylation modifications were partially retained, resulting in phenotypic differences in the offspring. Furthermore, some of the spaceflight-induced heritable differentially methylated regions (DMRs) were retained. Changes in epigenetic modifications caused by spaceflight affected the growth of two future seed generations. Altogether, our research is helpful in better understanding the adaptation mechanism of plants to the spaceflight environment.
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Project description:Intimate partner violence is a ubiquitous and devastating phenomenon for which effective interventions and a clear etiological understanding are still lacking. A major risk factor for violence perpetration is childhood exposure to violence, prompting the proposal that social learning is a major contributor to the transgenerational transmission of violence. Using an animal model devoid of human cultural factors, we showed that male rats became highly aggressive against their female partners as adults after exposure to non-social stressful experiences in their youth. Their offspring also showed increased aggression toward females in the absence of postnatal father-offspring interaction or any other exposure to violence. Both the females that cohabited with the stressed males and those that cohabited with their male offspring showed behavioral (including anxiety- and depression-like behaviors), physiological (decreased body weight and basal corticosterone levels) and neurobiological symptoms (increased activity in dorsal raphe serotonergic neurons in response to an unfamiliar male) resembling the alterations described in abused and depressed women. With the caution required when translating animal work to humans, our findings extend current psychosocial explanations of the transgenerational transmission of intimate partner violence by strongly suggesting an important role for biological factors.
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Project description:Epigenetic transgenerational inheritance potentially impacts disease etiology, phenotypic variation, and evolution. An increasing number of environmental factors from nutrition to toxicants have been shown to promote the epigenetic transgenerational inheritance of disease. Previous observations have demonstrated that the agricultural fungicide vinclozolin and pesticide DDT (dichlorodiphenyltrichloroethane) induce transgenerational sperm epimutations involving DNA methylation, ncRNA, and histone modifications or retention. These two environmental toxicants were used to investigate the impacts of parent-of-origin outcross on the epigenetic transgenerational inheritance of disease. Male and female rats were collected from a paternal outcross (POC) or a maternal outcross (MOC) F4 generation control and exposure lineages for pathology and epigenetic analysis. This model allows the parental allelic transmission of disease and epimutations to be investigated. There was increased pathology incidence in the MOC F4 generation male prostate, kidney, obesity, and multiple diseases through a maternal allelic transmission. The POC F4 generation female offspring had increased pathology incidence for kidney, obesity and multiple types of diseases through the paternal allelic transmission. Some disease such as testis or ovarian pathology appear to be transmitted through the combined actions of both male and female alleles. Analysis of the F4 generation sperm epigenomes identified differential DNA methylated regions (DMRs) in a genome-wide analysis. Observations demonstrate that DDT and vinclozolin have the potential to promote the epigenetic transgenerational inheritance of disease and sperm epimutations to the outcross F4 generation in a sex specific and exposure specific manner. The parent-of-origin allelic transmission observed appears similar to the process involved with imprinted-like genes.
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Project description:Environmental contamination by endocrine-disrupting chemicals (EDC) can have epigenetic effects (by DNA methylation) on the germ line and promote disease across subsequent generations. In natural populations, both sexes may encounter affected as well as unaffected individuals during the breeding season, and any diminution in attractiveness could compromise reproductive success. Here we examine mate preference in male and female rats whose progenitors had been treated with the antiandrogenic fungicide vinclozolin. This effect is sex-specific, and we demonstrate that females three generations removed from the exposure discriminate and prefer males who do not have a history of exposure, whereas similarly epigenetically imprinted males do not exhibit such a preference. The observations suggest that the consequences of EDCs are not just transgenerational but can be "transpopulational", because in many mammalian species, males are the dispersing sex. This result indicates that epigenetic transgenerational inheritance of EDC action represents an unappreciated force in sexual selection. Our observations provide direct experimental evidence for a role of epigenetics as a determinant factor in evolution.
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