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

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.