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

Author

Listed:
  • Mathew Pette

    (Imperial College London, Hammersmith Hospital Campus)

  • Andrew Dimond

    (Imperial College London, Hammersmith Hospital Campus)

  • António M. Galvão

    (The Babraham Institute
    Department of Reproductive Immunology and Pathology
    University of Cambridge)

  • 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
    University of Cambridge
    Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories)

  • Amanda G. Fisher

    (Imperial College London, Hammersmith Hospital Campus)

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.

Suggested Citation

  • 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., 2022. "Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30022-2
    DOI: 10.1038/s41467-022-30022-2
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    References listed on IDEAS

    as
    1. Bernhard Horsthemke, 2018. "A critical view on transgenerational epigenetic inheritance in humans," Nature Communications, Nature, vol. 9(1), pages 1-4, December.
    2. Sacri R. Ferrón & Marika Charalambous & Elizabeth Radford & Kirsten McEwen & Hendrik Wildner & Eleanor Hind & Jose Manuel Morante-Redolat & Jorge Laborda & Francois Guillemot & Steven R. Bauer & Isabe, 2011. "Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis," Nature, Nature, vol. 475(7356), pages 381-385, July.
    3. Fran Supek & Matko Bošnjak & Nives Škunca & Tomislav Šmuc, 2011. "REVIGO Summarizes and Visualizes Long Lists of Gene Ontology Terms," PLOS ONE, Public Library of Science, vol. 6(7), pages 1-9, July.
    4. Azusa Inoue & Lan Jiang & Falong Lu & Tsukasa Suzuki & Yi Zhang, 2017. "Maternal H3K27me3 controls DNA methylation-independent imprinting," Nature, Nature, vol. 547(7664), pages 419-424, July.
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