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Plate IV.387 · Publications

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

Article in The EMBO Journal, 26 September 2018.

Open accessStem Cells, Lineage

  1. Julia Tischler
  2. Wolfram H Gruhn
  3. John Reid
  4. Edward Allgeyer
  5. Florian Buettner
  6. Carsten Marr
  7. Fabian Theis
  8. Ben D Simons
  9. Lorenz Wernisch
  10. M Azim Surani

Abstract

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.

Cite

@article{tischler2018metabolic,
  title = {{Metabolic regulation of pluripotency and germ cell fate through α‐ketoglutarate}},
  author = {Tischler, Julia and Gruhn, Wolfram H and Reid, John and Allgeyer, Edward and Buettner, Florian and Marr, Carsten and Theis, Fabian and Simons, Ben D and Wernisch, Lorenz and Surani, M Azim},
  journal = {The EMBO Journal},
  publisher = {Springer Science and Business Media LLC},
  year = {2018},
  month = sep,
  doi = {10.15252/embj.201899518},
  url = {https://doi.org/10.15252/embj.201899518},
  pmid = {30257965},
  pmcid = {PMC6315289}
}
.bib file