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

EMBO J. 38:e99518 (2019)
Publishers Version DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
as soon as is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Cell State Transitions ; Germ Cells ; Metabolism ; Pseudotime Analysis ; Single-cell Analysis; Ground-state; Stem-cells; Specification; Naive; Differentiation; Activation; Transition; Induction; Dynamics; Patterns
Reviewing status