The role of Polycomb group proteins in mouse pre-implantation development

At the onset of life, two highly specialized gametes fuse to give rise to a totipotent embryo, which has the potential to differentiate into all tissues of the adult organism. This process is governed by transcriptional networks that arise during pre-implantation development and is orchestrated by dynamic changes in DNA methylation, chromatin organization and histone modifications. In my thesis, I addressed the role of the evolutionarily conserved Polycomb group (PcG) proteins for embryonic development and gene regulation during mouse pre-implantation development.
We demonstrated that genetic ablation of a core component of Polycomb repressive complex 2 (PRC2) affects gene expression and dosage compensation in early embryos. We have shown that besides dynamically regulating genes involved in development and differentiation at different stages of pre-implantation development, PRC2 also represses a subset of genes specifically on the maternal allele in early embryos. This allele-specific gene repression depends on the function of PRC2 in the oocyte, indicating that at these genes the H3K27me3 mark is inherited from oocytes to early embryos. We found that among the genes regulated in this fashion is the X inactivation regulator Xist, suggesting that H3K27me3 is the maternal repressive imprint that prevents inactivation of the maternal X chromosome in pre-implantation embryos. I have shown that although embryos maternally and zygotically deficient for PRC2 are able to develop to the blastocyst stage, they exhibit differences in the expression of lineage markers. Moreover, I demonstrated that maternal deletion of PRC2 impairs post-implantation development.
We further discovered that Polycomb repressive complex 1 (PRC1) represses a set of genes with functions in germ line development in early embryos. In embryonic stem cells (ESCs), these genes are regulated by DNA methylation as well as the variant PRC1 complex PRC1.6, suggesting that in pre-implantation embryos, where DNA methylation levels are low, PRC1.6 functions as a backup mechanism for repression of germ line genes. We are currently validating our hypothesis in embryos deficient for components of the PRC1.6 complex.
In summary, our work demonstrates that Polycomb group proteins function as dynamic regulators of gene expression in pre-implantation embryos in vivo.