https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=31991105&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 319911052020021820211204
1878-15515222020Jan27Developmental cellDev CellMetabolic Control over mTOR-Dependent Diapause-like State.236250.e7236-250.e710.1016/j.devcel.2019.12.018S1534-5807(19)31067-6Regulation of embryonic diapause, dormancy that interrupts the tight connection between developmental 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 reversible 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 suggest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state.Copyright © 2020 Elsevier Inc. All rights reserved.HusseinAbdiasis MAMDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.WangYuliangYInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.MathieuJulieJDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.MargarethaLilyanaLInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Molecular and Cellular Biology, University of Washington, Seattle, WA 98109, USA.SongChaozhongCInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine, Division of Hematology, University of Washington, Seattle, WA 98195, USA.JonesDaniel CDCPaul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.CavanaughChristopherCInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.MiklasJason WJWInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.MahenElisabethEInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine, Division of Hematology, University of Washington, Seattle, WA 98195, USA.ShowalterMegan RMRWest Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.RuzzoWalter LWLPaul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.FiehnOliverOWest Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.WareCarol BCBInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.BlauC AnthonyCAInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine, Division of Hematology, University of Washington, Seattle, WA 98195, USA.Ruohola-BakerHanneleHDepartment of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: hannele@uw.edu.engP01 GM081619GMNIGMS NIH HHSUnited StatesR01 GM083867GMNIGMS NIH HHSUnited StatesR01 GM097372GMNIGMS NIH HHSUnited StatesJournal Article
United StatesDev Cell1011200281534-58070Amino Acid Transport System A0Slc38a1 protein, mouseEC 2.7.11.1Mechanistic Target of Rapamycin Complex 2EC 2.7.11.1Protein Serine-Threonine KinasesEC 2.7.11.1Stk11 protein, mouseEC 2.7.11.31AMP-Activated Protein KinasesIMAMP-Activated Protein KinasesAmino Acid Transport System AmetabolismAnimalsBlastocystmetabolismCell ProliferationgeneticsphysiologyEmbryo, MammaliancytologyEmbryonic Stem CellscytologyGene Knockout TechniquesMechanistic Target of Rapamycin Complex 2metabolismMiceProtein Serine-Threonine KinasesmetabolismH4K16AcLKB1amino acidsdiapauseepigeneticsglutamine transporterlipolysismTORmetabolismpluripotent stem cellsDeclaration of Interests The authors declare no competing interests.2018119201991320191219202012960202012960202021960202057ppublish31991105NIHMS1552815PMC720439310.1016/j.devcel.2019.12.018S1534-5807(19)31067-6Ackerman D, Tumanov S, Qiu B, Michalopoulou E, Spata M, Azzam A, Xie H, Simon MC, and Kamphorst JJ (2018). 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