Defining the epigenetic principles that instruct the development of human embryos

Epigenetic processes create opportunities in development for safeguarding and directing cell state, particularly by the activity of Polycomb proteins and associated histone modifications. Determining how these mechanisms control cellular plasticity and lineage decisions in human embryos has fundamental biological importance with wide-reaching clinical implications. However, progress has been hampered by challenges associated with examining histone modifications over the first 14 days of human embryo development. This has led to a critical knowledge gap about how epigenetic mechanisms control the development of early human embryos, which we will directly address in this research programme. First, we will determine the epigenetic basis of developmental plasticity in preimplantation human embryogenesis by examining the dynamics of histone modification changes and by modulating Polycomb activity that we predict will disable cellular plasticity at these development stages. Second, using a novel assembloid system to support the faithful development of postimplantation human embryos, we will investigate the establishment and robustness of multilineage priming mechanisms in early postimplantation development. Third, we will test our mechanistic leads on a new role for specific Polycomb complexes in safeguarding epiblast transitions. Altogether, this programme will make vital advances in our understanding of the molecular principles that instruct early human embryogenesis.