2. Academic Validation
  3. Metabolic Control over mTOR-Dependent Diapause-like State

Metabolic Control over mTOR-Dependent Diapause-like State

  • Dev Cell. 2020 Jan 27;52(2):236-250.e7. doi: 10.1016/j.devcel.2019.12.018.
Abdiasis M Hussein 1,  Yuliang Wang 2,  Julie Mathieu 3,  Lilyana Margaretha 4,  Chaozhong Song 5,  Daniel C Jones 6,  Christopher Cavanaugh 7,  Jason W Miklas 8,  Elisabeth Mahen 5,  Megan R Showalter 9,  Walter L Ruzzo 10,  Oliver Fiehn 9,  Carol B Ware 7,  C Anthony Blau 5,  Hannele Ruohola-Baker 11
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
  • 2 Institute 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.
  • 3 Department 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.
  • 4 Institute 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.
  • 5 Institute 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.
  • 6 Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.
  • 7 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.
  • 8 Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
  • 9 West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.
  • 10 Paul 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.
  • 11 Department 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: [email protected].
PMID: 31991105 DOI: 10.1016/j.devcel.2019.12.018
Abstract

Regulation 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.

Keywords

H4K16Ac; LKB1; amino acids; diapause; epigenetics; glutamine transporter; lipolysis; mTOR; metabolism; pluripotent stem cells.

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