27 - 30 May 2005

EARLY-EMBRYONIC ACQUISITION AND LINEAGE-SPECIFIC MAINTENANCE OF IMPRINTED GENE REPRESSION David Umlauf [1], Alexandre Wagschal [1], Yuji Goto [3], Ru Cao[2], Yi Zhang [2] and Robert Feil [1] [1] Institute of Molecular Genetics CNRS UMR-5535 and University of Montpellier-II 1919, route de Mende F-34090 Montpellier France [2] Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill, NC 27599-7295 USA [3] Horizontal Medical Research Organisation Kyoto University Medical School Kyoto Japan

Genomic imprinting is a developmental mechanism that leads to mono-allelic expression of genes dependent on whether the allele is inherited from the mother or the father. Imprinted genes play important roles in extra-embryonic and embryonic development, are largely conserved between humans and mice, and are clustered in large chromosomal domains. Their allelic repression is brought about by ‘imprinting control regions’ (ICRs). All known ICRs are marked by parental allele-specific DNA methylation, an epigenetic modification which is essential for the maintenance of imprinting in the developing embryo.

To explore how imprinting is regulated in the trophoblast, we studied the Kcnq1 domain on distal mouse chromosome 7. This large domain comprises multiple genes that are imprinted in the placenta, without the apparent involvement of promoter DNA methylation. Imprinting along the domain is controlled by an intronic ICR, which acquires its maternal DNA methylation upon passage through the female germ line. We find that the ICR-mediated imprinting along the paternal chromosome involves acquisition of lysine-27 and lysine-9 methylation on histone H3. Polycomb repressive complexes are recruited to the paternal chromosome and potentially regulate this repressive histone methylation.

Studies on stem cells and pre-implantation embryos indicate that the repressive histone methylation is established before implantation and is maintained in the trophoblast lineage. In the embryo proper, however, imprinting is stably maintained only at genes that acquire promoter DNA methylation. These data underscore the importance of histone methylation (rather than DNA methylation) in imprinting in the placenta and reveal striking mechanistic similarities with imprinted X chromosome inactivation in the trophoblast. In addition, our findings might explain why in several studies placental imprinting was found to be particularly affected by early-embryonic manipulation and culture.

List of abstracts from the 3rd International Conference on the Female Reproductive Tract