Elucidating the role of nuclear metabolism in embryo implantation

Embryogenesis involves dynamic epigenetic and transcriptional changes as the zygote divides and cells differentiate into embryonic (epiblast) and extra-embryonic (primitive endoderm and trophectoderm) lineages.

Metabolites serve as cofactors or substrates for chromatin-modifying proteins, thus shaping the global epigenetic landscape.

Intriguingly, during early development, multiple metabolic enzymes translocate to the nucleus where they might fuel chromatin modifiers. How the interplay between nuclear metabolism and epigenetics regulates cell fate transitions remains unclear.

With this proposal, I aim to unveil the role of nuclear metabolism in regulating lineage-specific phenotypes during early development, using implantation as a model. I will focus on this developmental stage as it is characterised by dynamic metabolic and chromatin rewiring.

Since implantation relies on proper trophectoderm specification and maturation, I will use embryonic stem cell-derived trophoblast stem cells that transit between pre- and post-implantation-like states in vitro.

Specifically, I will establish novel tools to target the degradation of key metabolic enzymes exclusively in the nucleus and assess the impact on gene expression and chromatin modifications. Moreover, I propose to identify the genomic targets and protein partners of nuclear metabolic enzymes.

Ultimately, the integration of transcriptomic, genomic, and epigenomic data will unveil the metabolic determinants underlying gene expression and epigenetic changes at implantation.