Metabolic remodeling during murine early embryo development

Abstract During early mammalian embryogenesis, dynamic changes in cell growth and proliferation are tightly linked to the underlying genetic and metabolic regulation. However, our understanding of metabolic reprogramming and its impact on epigenetic regulation in early embryo development remains elusive 1. Here, we profiled metabolomes of embryos from the 2-cell and blastocyst stages, and their in vitro counterpart 2-cell like cells and ES cells, and reconstructed their metabolic landscape through the transition from totipotency to pluripotency. Our integrated metabolomics and transcriptomics analysis showed that 2-cell embryos favor methionine, polyamine and glutathione metabolism and stay in a more reductive state, whereas blastocyst embryos have higher mitochondrial TCA cycle metabolites and are in a more oxidative state. Moreover, we identify a reciprocal relationship between α-ketoglutarate (α-KG) and the competitive inhibitor of α-KG-dependent dioxygenases L-2-hydroxyglutarate (2-HG)2, namely, higher L-2-HG in the 2-cell embryos inherited from oocytes and 1-cell zygotes, and higher α-KG in the blastocyst. Supplementing 2-HG or knocking down L2hgdh, a gene encoding the 2-HG consuming enzyme L-2-hydroxyglutarate dehydrogenase 3 impeded erasure of global histone methylation markers 4–6. Together, our data demonstrate dynamic and interconnected metabolic, transcriptional and epigenetic network remodeling during murine early embryo development.