The role of polycomb repressive complex 2 in mouse preimplantation development

Abstract

Pluripotency is the ability of a cell to differentiate into any of the embryonic germ layers and is therefore referred to as the ground state of development. The totipotent/pluripotent state represents a bridge between generations – on one hand, it is initiated by the fusion of the two gametes that represent the previous generation, and on the other hand it gives rise to the germline of the next generation. Studies in model systems suggest that pluripotency is governed by a core transcriptional network that arises during mammalian preimplantation development, in a process accompanied by dynamic changes in chromatin organization, histone modifications and DNA methylation. In my thesis, I addressed the developmental and regulatory role of the evolutionary conserved Polycomb Repressive Complex 2 (PRC2) at the interface between two generations – in the oocyte and the preimplantation embryo. I demonstrated that genetic ablation of core members of PRC2 has an effect on H3K27me3 in vivo, and leads to a developmental and transcriptional response in late oocytes and early embryos. Furthermore, the observed mutant phenotypes revealed a dosage-dependent requirement for PRC2/H3K27me3 in the preimplantation embryo. I also found genetic evidence for an interplay between the two major Polycomb complexes, PRC1 and PRC2, in preimplantation embryos. I further described the transcriptional dynamics during early embryonic development of genes encoding chromatin modifiers. This single-cell profiling study highlighted the existence of maternal and embryonic variants of the major chromatin modifying complexes. In summary, my work reveals an important role of chromatin-based regulation in the preparation and acquisition of totipotency in vivo, manifested by a dosage-dependent PRC2/H3K27me3 requirement during the maternal-to-zygotic transition.