Uncovering the mechanistic basis for trophectoderm lineage commitment during mammalian pre-implantation development

The life of mammals starts with fertilization of an egg, which subsequently undergoes multiple rounds of cell division and develops into a complex multicellular organism. The first lineage segregation involves cells segregating to the inner cell mass (ICM) and trophectoderm (TE). Lineage-defining transcription factors (TFs), including CDX2 and GATA3, play a key role in establishing the gene regulatory networks that define these cell types. How they achieve this is poorly understood, in part due to the scarcity of cells during these early stages of development. In this proposal, I will apply my unique combination of expertise in low cell number functional genomics and biochemistry to reveal the molecular mechanisms by which TFs drive TE lineage commitment in mouse embryos. I will (1) define the mechanisms of transcriptional and epigenetic regulation during the sequential process of TE cell differentiation, (2) identify co-factors that modulate the action of TFs in specifying TE both as activators and repressors, and (3) determine how TFs engage with chromatin during gene activation and repression. The principles uncovered in this study will inform future studies of human development and further understanding of why inefficiency in the early stages of development is often a cause of infertility.