Title: Metabolic and Epigenetic Regulation in Embryonic Diapause

Abstract: Regulation of embryonic diapause, dormancy that interrupts the tight connection between developmental stage and time, is still poorly understood. We characterized the transcriptional and metabolite profiles of mouse diapause embryos and identified unique gene expression and metabolic signatures with activated lipolysis, glycolysis, and metabolic pathways regulated by AMPK. Starvation in pre-implantation ICM-derived mouse ESCs induces a reversible dormant state, transcriptionally mimicking the in vivo diapause stage. During starvation, Lkb1, an upstream kinase of AMPK, represses mTOR, inducing a reversible glycolytic and epigenetically H4K16Ac-negative, diapause-like state. Diapause furthermore activates expression of glutamine transporters SLC38A1/2.  We have shown by genetic and small molecule inhibitors that SLC38A1/2 are essential for diapause state. These data suggest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state. We recently found that mTOR-regulated mitophagy is required to initiate quiescence in human induced pluripotent stem cells (hiPSCs) by depleting Cyclin E on the mitochondrial surface. We will now dissect the mechanism for cyclin E degradation in the system.