Metabolic control over mTOR dependent diapause-like state

Regulation of embryonic diapause, dormancy that interrupts the tight connection between develop- mental stage and time, is still poorly understood. Here, we characterize the transcriptional and metabolite profiles of mouse diapause embryos and identify unique gene expression and metabolic signatures with activated lipolysis, glycolysis, and metabolic pathways regulated by AMPK. Lipolysis is increased due to mTORC2 repression, increasing fatty acids to support cell survival. We further show that 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, which induces a revers- ible glycolytic and epigenetically H4K16Ac-negative, diapause-like state. Diapause furthermore activates expression of glutamine transporters SLC38A1/2. We show by genetic and small molecule inhibitors that glutamine transporters are essential for the H4K16Ac-negative, diapause state. These data sug- gest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state. We did RNA-seq of Inner cell mass (ICM), diapause (dICM) and post-implantation (EPI) mouse embryos.