Metabolic Control over mTOR-Dependent Diapause-like State.

AMP-Activated Protein Kinases Amino Acid Transport System A / metabolism Animals Blastocyst / metabolism Cell Proliferation / genetics Embryo, Mammalian / cytology Embryonic Stem Cells / cytology Gene Knockout Techniques Mechanistic Target of Rapamycin Complex 2 / metabolism Mice Protein Serine-Threonine Kinases / metabolism
H4K16Ac LKB1 amino acids diapause epigenetics glutamine transporter lipolysis mTOR metabolism pluripotent stem cells

Journal

Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028

Informations de publication

Date de publication:
27 Jan 2020
Historique:
received: 09 11 2018
revised: 13 09 2019
accepted: 19 12 2019
entrez: 29 1 2020
pubmed: 29 1 2020
medline: 19 2 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.devcel.2019.12.018 PMID: 31991105 PMC: PMC7204393
pubmed: 31991105
pii: S1534-5807(19)31067-6
doi: 10.1016/j.devcel.2019.12.018
pmc: PMC7204393
mid: NIHMS1552815
pii:
doi:

Substances chimiques

Amino Acid Transport System A 0
Slc38a1 protein, mouse 0
Mechanistic Target of Rapamycin Complex 2 EC 2.7.11.1
Protein Serine-Threonine Kinases EC 2.7.11.1
Stk11 protein, mouse EC 2.7.11.1
AMP-Activated Protein Kinases EC 2.7.11.31

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

236-250.e7

Subventions

Organisme : NIGMS NIH HHS
ID : P01 GM081619
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM083867
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM097372
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Abdiasis M Hussein (AM)

Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.

Yuliang Wang (Y)

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.

Julie Mathieu (J)

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.

Lilyana Margaretha (L)

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.

Chaozhong Song (C)

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.

Daniel C Jones (DC)

Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.

Christopher Cavanaugh (C)

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.

Jason W Miklas (JW)

Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.

Elisabeth Mahen (E)

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.

Megan R Showalter (MR)

West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.

Walter L Ruzzo (WL)

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.

Oliver Fiehn (O)

West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA.

Carol B Ware (CB)

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.

C Anthony Blau (CA)

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.

Hannele Ruohola-Baker (H)

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: hannele@uw.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › AMP-Activated Protein Kinases › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Systèmes de transport d'acides aminés › Systèmes de transport d'acides aminés neutres › Système A de transport d'acides aminés › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Eucaryotes › Animaux › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Structures de l'embryon › Embryon de mammifère › Blastocyste › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Structures de l'embryon › Embryon de mammifère › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches embryonnaires › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Ciblage de gène › Techniques de knock-out de gènes › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-2 cible mécanistique de la rapamycine › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Metabolic Control over mTOR-Dependent...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Metabolic Control over mTOR-Dependent...