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An aberrant age of liver DNA methylation is associated with cloning-induced pathologies

Hélène Kiefer 1 Luc Jouneau 1 Evelyne Campion 1 Delphine Rousseau Ralliard 1 Thibaut Larcher 2 Marie-Laure Martin-Magniette 3, 4 Sandrine Balzergue 4 Mireille Ledevin 2 Audrey Prezelin 1 Pascale Chavatte-Palmer 1 Yvan Heyman 1 Christophe Richard 1, 5 Daniel Le Bourhis 6 Jean-Paul Renard 1 Hélène Jammes 1
1 BDR - Biologie du Développement et Reproduction
2 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
3 MIA-Paris - Mathématiques et Informatique Appliquées
4 IPS2 (UMR_9213 / UMR_1403) - Institut des Sciences des Plantes de Paris-Saclay
5 UE 1298 Unité Commune d'Expérimentation Animale
6 Allice
Abstract : It is postulated that the developmental defects frequently observed in somalie clones arise from inappropriate reprogramming of the donor epigenome by the oocyte. We used cattle clones as a model to investigate the long­ lerm effects of nuclear reprogramming on both DNA methylation and the phenotype of a differentiated organ, the liver. Pathological perinatal clones and apparently normal adult clones, both produced within one decade, were studied, together with age-matched controls. We identified differentially methylated regions (DMRs) in gene promoters displaying variations according to age and to the clone status of the animals. Strikingly, whereas adult clones did not differ significantly from adult controls, perinatal clones showed a demethylation at DMRs inconsistent with their chronological age. Pathological features were found in the liver of perinatal clones only, with histological lesions and modifications to both histomorphometrical and metabolic parameters. The integration of DMRs with phenotypic datasets led to the identification of epigenetic alterations correlated to phenotypic abnormalities in perinatal clones. Genes important to the antioxidant response and energy metabolism were targeted by these alterations. For at !east one DMR, the aberrant methylation profile in perinatal clones was associated with altered gene expression. The liver defects encountered in pathological perinatal clones could be associated to the aberrant age of DNA methylation, at genes indicating potential deficits in oxidative metabolism. We propose that epigenetic ageing is an adaptation to the excessive oxidative stress induced by reprogramming that the pathological clones were not able to counteract during subsequent developmental stages.
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Conference papers
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https://hal.inrae.fr/hal-02797595
Contributor : Migration Prodinra <>
Submitted on : Friday, June 5, 2020 - 2:56:13 PM
Last modification on : Friday, April 9, 2021 - 4:20:03 PM

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  • HAL Id : hal-02797595, version 1
  • PRODINRA : 343682

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INRAE | INRA | UNAM | AGROPARISTECH | UNIV-EVRY | CNRS | MIA-PARIS | UNIV-PARIS7 | UP-SCIENCES | USPC | UNIV-PARIS | IPS2 | BREED

Citation

Hélène Kiefer, Luc Jouneau, Evelyne Campion, Delphine Rousseau Ralliard, Thibaut Larcher, et al.. An aberrant age of liver DNA methylation is associated with cloning-induced pathologies. Conférence Jacques Monod, DNA methylation and demethylation, Centre National de la Recherche Scientifique (CNRS). FRA., Nov 2015, Roscoff, France. ⟨hal-02797595⟩

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