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

Van de Pette, Mathew, Dimond, Andrew, Galvão, António M., Millership, Steven J., To, Wilson, Prodani, Chiara, McNamara, Gráinne, Bruno, Ludovica, Sardini, Alessandro, Webster, Zoe, McGinty, James, French, Paul M. W., Uren, Anthony G., Castillo-Fernandez, Juan, Watkinson, William, Ferguson-Smith, Anne C., Merkenschlager, Matthias, John, Rosalind M., Kelsey, Gavin and Fisher, Amanda G. 2022. Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice. Nature Communications 13 (1) , 2464. 10.1038/s41467-022-30022-2

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 16 May 2022
Date of Acceptance: 13 April 2022
Last Modified: 19 May 2022 11:15
URI: https://orca.cardiff.ac.uk/id/eprint/149782

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