We are interested in the regulation of genomic imprinting in mammals, and in how this epigenetic mechanism influences embryonic and extra-embryonic development.
Our projects aim at unravelling the role of chromatin modifications and DNA methylation, and investigate the pathological deregulation of imprinting as a consequence of in vitro manipulation, and in human disease.
The word “epigenetic” is used to refer to heritable patterns of gene expression that occur without changes in the DNA sequence. Epigenetic mechanisms play important roles in animal and plant development. They are required to achieve stable gene silencing in defined cell types and at specific developmental stages. In mammals, there are many examples of epigenetic silencing of one of the two alleles of genes. These include X-chromosome inactivation in females, and imprinted genes, a group of genes whose expression depends on whether they are inherited from the mother or the father. Some eighty genes are now known to be imprinted in humans and mice. These are organised in large chromosomal clusters, and play important roles in embryonic and extra-embryonic development.
The allelic expression of imprinted genes is controlled by epigenetic marks, “the imprints”, which are put onto the gene in either female (egg) or male (sperm) germ cells. The precise nature of these imprints and the mechanisms that allow cells to distinguish the maternal and paternal copies of imprinted genes remain unclear. This said, DNA methylation is known to be essential for imprinting. However, DNA methylation alone does not provide the complete explanation for the establishment and maintenance of imprinted gene expression. Recent studies by our lab and others indicate that covalent modifications on histones are involved in imprinting as well, and are particularly important in the extra-embryonic lineages (placenta, yolk sac). This constitutes one of the group’s research themes. Our projects explore the involvement of specific histone methylation marks and use the mouse as a model system. We are also interested in the proteins that regulate “imprinting-control regions”. Here, our approaches include biochemical characterisation of putative imprinting factors, and transgenic mouse lines are used to explore their roles in vivo. A closely-related theme concerns the developmental control of imprints (germ line establishment, maintenance in the developing embryo). Together, these fundamental studies provide us with new insights into the mechanism of genomic imprinting. These are being applied within a third theme, namely the pathological deregulation of imprinting as a consequence of in vitro culture and manipulation, and in human disease.