Reprogrammation et épigenèse

Abstract

Les succès récents du clonage animal démontrent que le noyau d’une cellule somatique adulte différenciée peut retourner à un état de type embryonnaire, lui permettant de repasser par les étapes qui conduisent à la naissance d’un animal viable et normal. Même si les rendements restent très faibles, l’obtention de ces animaux illustre la plasticité extraordinaire du noyau et l’influence de son environnement cytoplasmique sur le profil d’expression des gènes. Seul jusqu’à présent le cytoplasme ovocytaire s’est montré capable d’induire une telle « reprogrammation». Les mécanismes moléculaires sous-jacents font désormais l’objet de nombreuses études, notamment pour comprendre les modifications des marques épigénétiques et les remaniements de structure chromatinienne impliqués dans cette reprogrammation. Cet article fait le point sur les principaux résultats obtenus par la mise en oeuvre de cette approche expérimentale qu’est le clonage.

The fact that the nucleus of a differentiated somatic cell can be reprogrammed in order to sustain embryonic development is now well established. Experiments of somatic cell nuclear transfer (cloning) have proved that a foreign nucleus introduced into an enucleated oocyte can give rise to physiologically normal offsprings, with a normal lifespan. Such evidence of genome expression plasticity is also observed experimentally with heterokaryons, created by the fusion or the nuclear transfer between two somatic cells, where differentiated nuclei are able to express genes characteristic of the host cell. However, the epigenetic mechanisms that permit nuclear plasticity remain poorly understood. In this paper we present the main evidences showing important modifications of the large scale organisation of chromosomal domains and of the DNA methylation pattern upon nuclear transfer and during the first cleavages. These modifications of epigenetic marks, brought by an intimate contact between the chromatin and the recipient oocyte cytoplasmic factors, appear essential for further development. They are established over the first cell cycles of development. The onset of embryonic genome activation and the first cellular differentiation events that occur over the implantation period are two additional check-points of reprogramming that appear to be also highly dependant on epigenetic alterations. Beyond those stages, defective placental functions might be directly responsible for the fetal and postnatal physiopathologies frequently observed in cloned animals. No direct link between preimplantation reprogramming defaults, placental disfunctions and low development to term has been established yet. The epigenetics studies which are now used to characterise loci specific and probably genotype dependant alterations in cloned animals of different species will provide unvaluable help to define the role of epigenesis in the achievement of a developmental program.