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

Mathew Pette, Andrew Dimond, António M. Galvão, Steven J. Millership, Wilson To, Chiara Prodani, Gráinne McNamara, Ludovica Bruno, Alessandro Sardini, Zoe Webster, James McGinty, Paul M. W. French, Anthony G. Uren, Juan Castillo-Fernandez, William Watkinson, Anne C. Ferguson-Smith, Matthias Merkenschlager, Rosalind M. John, Gavin Kelsey and Amanda G. Fisher ()
Additional contact information
Mathew Pette: Imperial College London, Hammersmith Hospital Campus
Andrew Dimond: Imperial College London, Hammersmith Hospital Campus
António M. Galvão: The Babraham Institute
Steven J. Millership: Imperial College London, Hammersmith Hospital Campus
Wilson To: Imperial College London, Hammersmith Hospital Campus
Chiara Prodani: Imperial College London, Hammersmith Hospital Campus
Gráinne McNamara: Imperial College London, Hammersmith Hospital Campus
Ludovica Bruno: Imperial College London, Hammersmith Hospital Campus
Alessandro Sardini: Imperial College London, Hammersmith Hospital Campus
Zoe Webster: Imperial College London, Hammersmith Hospital Campus
James McGinty: Imperial College London, South Kensington Campus
Paul M. W. French: Imperial College London, South Kensington Campus
Anthony G. Uren: Imperial College London, Hammersmith Hospital Campus
Juan Castillo-Fernandez: The Babraham Institute
William Watkinson: University of Cambridge, Downing Street
Anne C. Ferguson-Smith: University of Cambridge, Downing Street
Matthias Merkenschlager: Imperial College London, Hammersmith Hospital Campus
Rosalind M. John: Cardiff University
Gavin Kelsey: The Babraham Institute
Amanda G. Fisher: Imperial College London, Hammersmith Hospital Campus

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30022-2

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