Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE175536 | GEO | 2022/04/01
REPOSITORIES: GEO
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Project description:Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. In mammals, evidence supports similar trans- and inter-generational effects although the underlying mechanisms are incompletely understood. Here a luciferase knock-in reporter mouse for the imprinted Dlk1 locus was generated to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet (HFD) in pregnancy provoked sustained re-expression of the normally silent maternal Dlk1 allele in offspring (a loss of imprinting) and increased DNA methylation at the sDMR. In the next generation heterogeneous Dlk1 mis-expression was seen exclusively among animals born to F1-exposed females. Oocytes from these females showed altered gene and miR expression without changes in DNA methylation, and correct imprinting was restored in subsequent generations. Our results illustrate how diet impacts the foetal epigenome, disturbing canonical and non-canonical imprinting mechanisms to modulate the properties of two successive generations of offspring.
2022-04-01 | GSE175537 | GEO
Project description:We used microarrays to investigate the transcriptome of male flies exposed to either a rich or a poor nutrient environment during development. Further we investigated transcriptome of their offspring and grand-offspring also developed at poor or rich diet. The ability of organisms to cope with poor quality nutrition is essential for their persistence. For species with short generation time, the nutritional environments can transcend generations, making it beneficial for adults to prime their offspring to particular diets. However, our understanding of potential adaptive generational effects, including those of diet quality, is still very limited. Here we use the vinegar fly, Drosophila melanogaster, to investigate if females developing as larvae on a nutritionally poor diet produce offspring that are primed for nutrient deficiencies in the following generations. We found that females developed at low quality diets produced offspring, which at similarly low-quality diets had both increased egg-to-adult viability and starvation tolerance compared to females experiencing a nutrient rich diet in the previous generation. When testing the persistence of such generational priming, we found that just one generation of high-quality diet is sufficient to return performance to initial levels. A global transcriptomic profile analysis suggests that the observed phenotypic priming is not a constitutive transcriptomic adjustment, instead offspring appear primed to initiate an adaptive response only when exposed to low quality diets. Our results show that generational priming is likely an important adaptive mechanism of coping with transient nutritional fluctuations.
2023-07-12 | GSE236807 | GEO
Project description:Adult female Wistar rats (about 220g) obtained from a breeding colony were mated and fed either a protein sufficient (PS) or protein restricted (PR) diet (n = 6 per dietary group) during F0 pregnancy which provided an increase in energy of approximately 25% compared to the diet fed to the breeding colony (2018S). During lactation dams were fed AIN93G and litters were standardisied to 8 offspring within 24 hours of birth with a bias towards females. Offpsring were weaned onto AIN93M at postnatal day 28 and F1 and F2 females were mated on postnatal day 70 (n = 6 per F0 dietary group). F1 and F2 dams were fed the PS diet during pregnancy and AIN93G during lactation. Offspring were weaned onto AIN93M. On postnatal day 70 unmated female offspring were fasted for 12 hours then sacrificed for hepatic transcritpome analysis by microarray. Expression of 1,684 genes differed by at least 2 fold between adult female F1 offspring of F0 dams from both dietary groups. 1680 genes were altered in F2 offspring and 2,065 genes altered in F3 offspring. Expression of 113 genes was altered in all three generations. Of these, 47% showed directionally opposite differences between generations. Gene ontology analysis revealed clear differences in the pathways altered in each generation. F1 and F2 offspring of F0 dams fed a PR diet showed impaired fasting glucose homeostasis. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression was elevated in F1 and F2 offspring from F0 PR dams, but decreased in F3, compared to PS offspring
2011-06-01 | E-MEXP-3205 | biostudies-arrayexpress
Project description:Intralocus sexual conflict, where males and females have different fitness optima for the same trait, has been suggested to potentially be resolved by genomic imprinting, whereby expression in offspring is altered according to parent-of-origin. However, this idea has not yet been empirically tested. Here, we designed an experimental evolution protocol in Drosophila melanogaster which enabled us to look for imprinting effects on the X-chromosome. We enforced father-to-son transmission of the X-chromosome for many generations, and compared fitness and gene expression levels between control males, males with a control X-chromosome that had undergone one generation of father-son transmission (CDX), and males with an X-chromosome that had undergone many generations of father-son transmission (MLX). Although fitness differences were consistent with lowered fitness of males with a paternally inherited X-chromosome, expression differences suggested that this was due to deleterious maternal effects rather than imprinting. We conclude that imprinting is unlikely to resolve intralocus sexual conflict in Drosophila melanogaster. 18 samples were analyzed. There were 3 replicate populations within each of 3 treatments (Control, CDX, and MLX), and two males were analyzed from each population, for a total of 18 males.
2012-04-16 | E-GEOD-37325 | biostudies-arrayexpress
Project description:Intralocus sexual conflict, where males and females have different fitness optima for the same trait, has been suggested to potentially be resolved by genomic imprinting, whereby expression in offspring is altered according to parent-of-origin. However, this idea has not yet been empirically tested. Here, we designed an experimental evolution protocol in Drosophila melanogaster which enabled us to look for imprinting effects on the X-chromosome. We enforced father-to-son transmission of the X-chromosome for many generations, and compared fitness and gene expression levels between control males, males with a control X-chromosome that had undergone one generation of father-son transmission (CDX), and males with an X-chromosome that had undergone many generations of father-son transmission (MLX). Although fitness differences were consistent with lowered fitness of males with a paternally inherited X-chromosome, expression differences suggested that this was due to deleterious maternal effects rather than imprinting. We conclude that imprinting is unlikely to resolve intralocus sexual conflict in Drosophila melanogaster.
2012-04-17 | GSE37325 | GEO
Project description:The prevalence of obesity has steadily increased since decades. In the meantime, in line with the exposition of populations of from industrialized countries have been exposed to fat-rich diet with high exaggerated ù6/ù3 ratio of ù6- over ù3-polyunsaturated fatty acids. To assess the contribution of dietary fatty acids, male and female mice fed a human-like fat diet were mated randomly and maintained after breeding on the same diet for successive generations. Offspring showed over 4 generations a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in energy intake. Transgenerational alterations in adipokine levels were accompanied by hyperinsulinemia. When switched to a standard diet, the obese phenotype (termed revHF4) reversed partially. Offspring of revHF4 mice exhibited higher birth weight and faster gain weight compared to control mice. Gene expression analyses of the stromal vascular fraction of adipose tissue over generations revealed i) underexpression of genes favoring angiogenesis and controlling oxidative stress and ii) overexpression of genes involved in inflammation, and in adipogenesis .and in insulin resistance. Thus, under conditions of genome stability, our results show that metabolic imprinting induced by a human-like fat diet is accompanied by a gradual fat mass enhancement, in accordance with the increasing prevalence of obesity observed in humans over generations.
2010-06-01 | GSE16636 | GEO
Project description:Maternal exposures during pregnancy influence the risk of many chronic adult-onset diseases in the offspring. We investigated whether feeding pregnant rats a high fat (HF) or ethinyl-estradiol (EE2)-supplemented diet affects carcinogen-induced mammary cancer risk in daughters, granddaughters and great-granddaughters. Here we show that mammary tumorigenesis is higher in daughters and granddaughters of HF rat dams and in daughters, granddaughters and great-granddaughters of EE2 rat dams. Outcross experiments indicate that increased mammary cancer risk is transmitted to HF granddaughters equally through the female or male germlines, but it is only transmitted to EE2 granddaughters through the female germline. The effects of maternal EE2 exposure on offspring's mammary cancer risk are associated with alternations in the DNA methylation machinery and methylation patterns in mammary tissue of all three EE2 generations. We conclude that dietary and estrogenic exposures in pregnancy increase breast cancer risk in multiple generations of offspring, possibly through non-genetic means We examined the whole genome methylation status of both control and EE2-supplemented diet rats in three consecutive generations
2012-09-20 | E-GEOD-40251 | biostudies-arrayexpress
Project description:Dysregulation of imprinted gene loci also referred to as loss of imprinting (LOI) can result in severe developmental defects and other diseases, but the molecular mechanisms that ensure imprint stability remain incompletely understood. Here, we dissect the functional components of the imprinting control region of the essential Dlk1-Dio3 locus (called IG-DMR) and the mechanism by which they ensure imprinting maintenance. Using pluripotent stem cells carrying an allele-specific reporter system, we demonstrate that the IG-DMR consists of two antagonistic regulatory elements: a paternally methylated CpG-island that prevents the activity of Tet dioxygenases and a maternally unmethylated regulatory element, which serves as a non-canonical enhancer and maintains expression of the maternal Gtl2 lncRNA by precluding de novo DNA methyltransferase function. Targeted genetic or epigenetic editing of these elements leads to LOI with either bi-paternal or bi-maternal expression patterns and respective allelic changes in DNA methylation and 3D chromatin topology of the entire Dlk1-Dio3 locus. Although the targeted repression of either IG-DMR or Gtl2 promoter is sufficient to cause LOI, the stability of LOI phenotype depends on the IG-DMR status, suggesting a functional hierarchy. These findings establish the IG-DMR as a novel type of bipartite control element and provide mechanistic insights into the control of Dlk1-Dio3 imprinting by allele-specific restriction of the active DNA (de)methylation machinery.
2021-09-14 | GSE148315 | GEO
Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.
2012-12-29 | E-GEOD-43187 | biostudies-arrayexpress
Project description:RRBS was used to analyse global imprinting gene methylation pattern of offspring from the in vitro derived spermatids like cells and normal control Global imprinting gene methylation pattern comparision of two offspring (one male and one female) from the in vitro derived spermatids like cells and two normal control mice (one male and one female)
2016-02-26 | E-GEOD-76238 | biostudies-arrayexpress