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Metabolic regulation of pluripotency and germ cell fate through alpha-ketoglutarate.

EMBO J. 38:e99518 (2019)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 naive 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 naive 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 naive 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cell State Transitions ; Germ Cells ; Metabolism ; Pseudotime Analysis ; Single-cell Analysis; Ground-state; Stem-cells; Specification; Naive; Differentiation; Activation; Transition; Induction; Dynamics; Patterns
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Zeitschrift EMBO Journal, The
Quellenangaben Band: 38, Heft: 1, Seiten: , Artikelnummer: e99518 Supplement: ,
Verlag Wiley
Verlagsort Heidelberg, Germany