title: Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies.
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.
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Kiefer
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Jouneau
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Évelyne
authors.initials: É
authors.lastname: Campion
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rousseau-Ralliard
authors.affiliation: INRA, UMR0703 APEX, Oniris, Nantes, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Larcher
authors.affiliation: UMR MIA-Paris, AgroParisTech, INRA, Université Paris-Saclay, 75005, Paris, France.|Institute of Plant Sciences Paris Saclay IPS2, CNRS, INRA, Université Paris-Sud, Université Evry, Université Paris-Saclay, 91405 Orsay, France.|Institute of Plant Sciences Paris-Saclay IPS2, Paris Diderot, Sorbonne Paris-Cité, Bâtiment 630, 91405, Orsay, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Martin-Magniette
authors.affiliation: Institute of Plant Sciences Paris Saclay IPS2, CNRS, INRA, Université Paris-Sud, Université Evry, Université Paris-Saclay, 91405 Orsay, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Balzergue
authors.affiliation: INRA, UMR0703 APEX, Oniris, Nantes, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Ledevin
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Prézelin
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Chavatte-Palmer
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Heyman
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.|INRA, UE1298, Unité Commune d'Expérimentation Animale, Leudeville, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Richard
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Le Bourhis
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Renard
authors.affiliation: UMR BDR, INRA, ENVA, Université Paris Saclay, 78350, Jouy en Josas, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Jammes
mesh_terms: D000818:Animals; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019976:Cloning, Organism; D019175:DNA Methylation; D004195:Disease Models, Animal; D004734:Energy Metabolism; D044127:Epigenesis, Genetic; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010641:Phenotype; D013312:Stress, Physiological
chemical_list: D005227:Fatty Acids