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Tischler, J.* ; Gruhn, W.H.* ; Reid, J.* ; Allgeyer, E.* ; Buettner, F. ; Marr, C. ; Theis, F.J. ; Simons, B.D.* ; Wernisch, L.* ; Surani, M.A.*

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

EMBO J. 38:e99518 (2019)
Publ. Version/Full Text DOI
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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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
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Quellenangaben Volume: 38, Issue: 1, Pages: , Article Number: e99518 Supplement: ,
Publisher Wiley
Publishing Place Heidelberg, Germany
Reviewing status Peer reviewed