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Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice [BS-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE175537 | GEO | 2022/04/01

REPOSITORIES: GEO

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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.

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Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice [BS-seq]

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