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

de Pette M Van; 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; Amanda G. Fisher

doi:10.1038/s41467-022-30022-2

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

de Pette M Van, 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, Amanda G. Fisher^*

^*Corresponding author for this work

School of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

AbstractTransmission 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 imprintedDlk1locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternalDlk1in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneousDlk1mis-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.

Original language	English
Number of pages	0
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30022-2
Publication status	E-pub ahead of print - 5 May 2022

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Van, D. P. M., Dimond, A., Galvão, A. M., Millership, S. J., To, W., Prodani, C., McNamara, G., Bruno, L., Sardini, A., Webster, Z., McGinty, J., French, P. M. W., Uren, A. G., Castillo-Fernandez, J., Watkinson, W., Ferguson-Smith, A. C., Merkenschlager, M., John, R. M., Kelsey, G., & Fisher, A. G. (2022). Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice. Nature Communications, 13(1). Advance online publication. https://doi.org/10.1038/s41467-022-30022-2

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title = "Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice",

abstract = "AbstractTransmission 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 imprintedDlk1locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternalDlk1in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneousDlk1mis-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.",

author = "Van, {de Pette M} and Andrew Dimond and Galv{\~a}o, {Ant{\'o}nio M.} and Millership, {Steven J.} and Wilson To and Chiara Prodani and Gr{\'a}inne McNamara and Ludovica Bruno and Alessandro Sardini and Zoe Webster and James McGinty and French, {Paul M.W.} and Uren, {Anthony G.} and Juan Castillo-Fernandez and William Watkinson and Ferguson-Smith, {Anne C.} and Matthias Merkenschlager and John, {Rosalind M.} and Gavin Kelsey and Fisher, {Amanda G.}",

year = "2022",

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doi = "10.1038/s41467-022-30022-2",

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Van, DPM, Dimond, A, Galvão, AM, Millership, SJ, To, W, Prodani, C, McNamara, G, Bruno, L, Sardini, A, Webster, Z, McGinty, J, French, PMW, Uren, AG, Castillo-Fernandez, J, Watkinson, W, Ferguson-Smith, AC, Merkenschlager, M, John, RM, Kelsey, G & Fisher, AG 2022, 'Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice', Nature Communications, vol. 13, no. 1. https://doi.org/10.1038/s41467-022-30022-2

TY - JOUR

T1 - Epigenetic changes induced by in utero dietary challenge result in phenotypic variability in successive generations of mice

AU - Van, de Pette M

AU - Dimond, Andrew

AU - Galvão, António M.

AU - Millership, Steven J.

AU - To, Wilson

AU - Prodani, Chiara

AU - McNamara, Gráinne

AU - Bruno, Ludovica

AU - Sardini, Alessandro

AU - Webster, Zoe

AU - McGinty, James

AU - French, Paul M.W.

AU - Uren, Anthony G.

AU - Castillo-Fernandez, Juan

AU - Watkinson, William

AU - Ferguson-Smith, Anne C.

AU - Merkenschlager, Matthias

AU - John, Rosalind M.

AU - Kelsey, Gavin

AU - Fisher, Amanda G.

PY - 2022/5/5

Y1 - 2022/5/5

N2 - AbstractTransmission 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 imprintedDlk1locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternalDlk1in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneousDlk1mis-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.

AB - AbstractTransmission 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 imprintedDlk1locus to visualise and track epigenetic fidelity across generations. Exposure to high-fat diet in pregnancy provokes sustained re-expression of the normally silent maternalDlk1in offspring (loss of imprinting) and increased DNA methylation at the somatic differentially methylated region (sDMR). In the next generation heterogeneousDlk1mis-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.

U2 - 10.1038/s41467-022-30022-2

DO - 10.1038/s41467-022-30022-2

M3 - Article

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

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