TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency

Metabolism has emerged as a crucial regulator of development and stem cell epigenome. This coupling is particularly evident during the in vitro exit from naïve pluripotency. However, our understanding of the dynamic metabolic rewiring at this developmental stage remains rudimentary. In this study, we reconstruct intracellular metabolite routings in pre- and post-implantation mouse embryos and their dynamic stem cell models. Our findings reveal that, instead of a simple TCA cycle shutdown, there is spatio-temporally programmed TCA cycle rewiring at implantation. Focusing on the pluripotency spectrum, we identify pyruvate as a key metabolic nexus. Indeed, pyruvate carboxylase and malic enzyme activity is essential for maintaining a balanced metabolic and transcriptional state as well as timely exit from naïve pluripotency. Additionally, we discover that formative and primed pluripotent cells exhibit increased glutamine uptake, reduced oxidative TCA activity, and reciprocal reductive glutamine metabolism. This metabolic rewiring supports increased histone acetylation turnover, primarily using glutamine as a carbon source, supplemented by pyruvate cycling. Thus, we uncover diverse nutrient strategies that are functionally coupled to epigenome programming and dynamic pluripotency cell state transitions at the time of implantation.