Metabolic regulation of pluripotency and germ cell fate through α‐ketoglutarate. (26th September 2018)

• Record Type: Journal Article
• Authors: Tischler, Julia; Gruhn, Wolfram H; Reid, John; Allgeyer, Edward; Buettner, Florian; Marr, Carsten; Theis, Fabian; Simons, Ben D; Wernisch, Lorenz; Surani, M Azim
• Is Part Of: EMBO journal. Volume 38:Number 1(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-09-26
• Subjects: cell state transitions -- germ cells -- metabolism -- pseudotime analysis -- single‐cell analysis; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201899518
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Investigations into the emerging link between metabolism and cellular identity during mouse early embryonic development reveal that the generation of alpha–ketoglutarate (αKG) by the mitochondrial TCA cycle enzyme IDH2 can modulate the epigenome, which, in turn, can maintain naïve pluripotency and prolong a transient competent state for primordial germ cell (PGC) specification. IDH2‐mediated production of αKG in the mitochondrial Krebs cycle promotes and maintains the epigenetic state of naïve pluripotent stem cells. αKG extends the transient state of developmental competence for the PGC fate. αKG supports the specification of mouse PGCs. Stabilisation of transient developmental states can occur through modulation of metabolic states of cells. Abstract : Oxidative mitochondrial metabolism and IDH2‐dependent α–ketoglutarate prolong a transient competent state for primordial germ cell specification.