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

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. A total of 78 MII oocytes, 41 from F1 mat-CD mice and 37 from F1 mat-HFD mice.