Metabolic regulation of pluripotency and germ cell fate through α‐ketoglutarate

• Julia Tischler ^[1] ; Wolfram H Gruhn ^[1] ; John Reid ^[2] ; Edward Allgeyer ^[1] ; Florian Buettner ^[3] ; Carsten Marr ^[3] ; Fabian Theis ^[4] ; Ben D Simons ^[1] ; Lorenz Wernisch ^[5] ; M Azim Surani ^[1]
  1. [1] University of Cambridge

     University of Cambridge

     Cambridge District, Reino Unido

     
  2. [2] 2 MRC Biostatistics Unit Cambridge Institute of Public Health University of Cambridge, Cambridge Biomedical Campus Cambridge UK; 3 The Alan Turing Institute British Library London UK
  3. [3] 4 Institute of Computational Biology Helmholtz Zentrum München‐German Research Center for Environmental Health Neuherberg Germany
  4. [4] 4 Institute of Computational Biology Helmholtz Zentrum München‐German Research Center for Environmental Health Neuherberg Germany; 5 Department of Mathematics Chair of Mathematical Modeling of Biological Systems Technische Universität München Garching Germany
  5. [5] 2 MRC Biostatistics Unit Cambridge Institute of Public Health University of Cambridge, Cambridge Biomedical Campus Cambridge UK

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 1, 2019, pág. 1
• Idioma: inglés
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  • An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an in vitro model for early mouse embryonic development: from naïve pluripotency to the specification of primordial germ cells (PGCs). Using single‐cell RNA‐seq with statistical modelling and modulation of energy metabolism, we demonstrate a functional role for oxidative mitochondrial metabolism in naïve pluripotency. We link mitochondrial tricarboxylic acid cycle activity to IDH2‐mediated production of alpha‐ketoglutarate and through it, the activity of key epigenetic regulators. Accordingly, this metabolite has a role in the maintenance of naïve pluripotency as well as in PGC differentiation, likely through preserving a particular histone methylation status underlying the transient state of developmental competence for the PGC fate. We reveal a link between energy metabolism and epigenetic control of cell state transitions during a developmental trajectory towards germ cell specification, and establish a paradigm for stabilizing fleeting cellular states through metabolic modulation.