Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies

Hélène Kiefer; Luc Jouneau; Evelyne Campion; Delphine Rousseau Ralliard; Thibaut Larcher; Marie-Laure Martin Magniette; Sandrine Balzergue; Mireille Ledevin; Audrey Prezelin; Pascale Chavatte-Palmer; Yvan Heyman; Christophe Richard; Daniel Le Bourhis; Jean-Paul Renard; Hélène Jammes

doi:10.1038/srep38869

Journal articles

Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies

Hélène Kiefer ^{1, 2} Luc Jouneau ^{1, 2} Evelyne Campion ^{1, 2} Delphine Rousseau Ralliard ^{1, 2} Thibaut Larcher ³ Marie-Laure Martin Magniette ⁴ Sandrine Balzergue ⁴ Mireille Ledevin ³ Audrey Prezelin ^{1, 2, *} Pascale Chavatte-Palmer ^{1, 2, *} Yvan Heyman ^{1, 2, *} Christophe Richard ^{1, 5, 2, *} Daniel Le Bourhis ¹ Jean-Paul Renard ^{1, 2} Hélène Jammes ^{1, 2}

* Corresponding author

1 BDR - Biologie du Développement et Reproduction

2 Université Paris Saclay (COmUE)

3 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux

4 IPS2 (UMR_9213 / UMR_1403) - Institut des Sciences des Plantes de Paris-Saclay

5 UE 1298 Unité Commune d'Expérimentation Animale

Abstract : Cloning enables the generation of both clinically normal and pathological individuals from the same donor cells, and may therefore be a DNA sequence-independent driver of phenotypic variability. We took advantage of cattle clones with identical genotypes but different developmental abilities to investigate the role of epigenetic factors in perinatal mortality, a complex trait with increasing prevalence in dairy cattle. We studied livers from pathological clones dying during the perinatal period, clinically normal adult clones with the same genotypes as perinatal clones and conventional age-matched controls. The livers from deceased perinatal clones displayed histological lesions, modifications to quantitative histomorphometric and metabolic parameters such as glycogen storage and fatty acid composition, and an absence of birth-induced maturation. In a genome-wide epigenetic analysis, we identified DNA methylation patterns underlying these phenotypic alterations and targeting genes relevant to liver metabolism, including the type 2 diabetes gene TCF7L2. The adult clones were devoid of major phenotypic and epigenetic abnormalities in the liver, ruling out the effects of genotype on the phenotype observed. These results thus provide the first demonstration of a genome-wide association between DNA methylation and perinatal mortality in cattle, and highlight epigenetics as a driving force for phenotypic variability in farmed animals.

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Journal articles

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Life Sciences [q-bio] / Development Biology

Life Sciences [q-bio] / Reproductive Biology

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