A single protein complex balances the very first lineage decision of cells in human: towards foetus or placenta

During development, the very early embryo is thought to be developmentally unrestricted, being able to differentiate into both embryonic (foetus) and extraembryonic (placental) lineages. This unrestricted developmental potential is thought to be facilitated by the lack of any chromatin-based lineage-barriers, representing a "blank slate". However, it has remained enigmatic how such blank slate of totipotent-like cells is manifested.

To comprehensively profile the epigenetic state of human naive (totipotent-like) embryonic cells, international group of researchers spearheaded by Dick Zijlmans and Hendrik Marks together with colleagues from KU Leuven, examined which proteins are associated with the chromatin and how this affects gene transcription. They observed a strong enrichment of the histone modification H3K27me3, which is deposited by polycomb repressive complex 2 (PRC2), and found this histone mark to be more abundantly present at the promotors of lineage-determining genes. By inhibiting PRC2, thereby preventing H3K27me3 deposition, the researchers observed enhanced formation of trophectoderm cells. Similarly, in a very recently developed human embryonic model called blastoids (see figure), they observed accelerated blastoid development and increased cavitation upon PRC2 inhibition, highlighting a role for PRC2 as a lineage gatekeeper during the earliest stages of human development. The results were published this week in Nature Cell Biology.

This new research opens up the ability to better control stem cell specialisation and blastoid development, which is useful for studying in the laboratory how the initial placental cells are formed. In the longer term, the new knowledge might improve our understanding of how embryos successfully implant in the uterus at the earliest stages of pregnancy, and how this can be misregulated.