Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice

Here the authors show that a high-fat diet in pregnant mice can release silencing of the imprinted Dlk1 locus in multiple generations of offspring. They found that this occurs via changes in microRNA expression at the locus of interest, as well as transcriptional changes across the genome, in the developing oocytes. Transmission of epigenetic information between generations occurs in nematodes, flies and plants, mediated by specialised small RNA pathways, modified histones and DNA methylation. Similar processes in mammals can also affect phenotype through intergenerational or trans-generational mechanisms. Here we generate a luciferase knock-in reporter mouse for the imprinted Dlk1 locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternal Dlk1 in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneous Dlk1 mis-expression is seen exclusively among animals born to F1-exposed females. Oocytes from these females show altered gene and microRNA expression without changes in DNA methylation, and correct imprinting is 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 successive generations of offspring.

Automated summary

This study demonstrates that a high-fat diet in pregnant mice can lead to the release of silencing of the Dlk1 gene locus in multiple generations of offspring. The authors found that this occurs through changes in microRNA expression and transcriptional changes in the developing oocytes. These findings highlight how diet can impact the fetal epigenome, affecting the properties of successive generations of offspring through intergenerational or trans-generational mechanisms.