Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.
Gruhn, Wolfram H
Simons, Ben D
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Tischler, J., Gruhn, W. H., Reid, J., Allgeyer, E., Buettner, F., Marr, C., Theis, F., et al. (2019). Metabolic regulation of pluripotency and germ cell fate through α-ketoglutarate.. EMBO J, 38 (1) https://doi.org/10.15252/embj.201899518
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.
Germ Cells, Cells, Cultured, Pluripotent Stem Cells, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Ketoglutaric Acids, Cell Differentiation, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Female, Male, Embryonic Stem Cells, Metabolic Networks and Pathways, Embryo, Mammalian
J.T. was supported by the Austrian Academy of Sciences, the Wellcome Trust, and the Swiss National Fund for Science, W.H.G. by EMBO and the Wellcome Trust, J.R. and L.W. by the UK Medical Research Council, and E.A. by the Wellcome Trust. M.A.S. is a Wellcome Senior Investigator. Work at the Gurdon Institute is supported by a core grant from the Wellcome Trust and Cancer Research UK.
Wellcome Trust (096738/Z/11/Z)
Wellcome Trust (098357/Z/12/Z)
Medical Research Council (MC_PC_12009)
Medical Research Council (MR/P009948/1)
External DOI: https://doi.org/10.15252/embj.201899518
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285394
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/