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

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.

Source: EMBO Journal - January 3, 2019 Category: Molecular Biology Authors: Tischler, J., Gruhn, W. H., Reid, J., Allgeyer, E., Buettner, F., Marr, C., Theis, F., Simons, B. D., Wernisch, L., Surani, M. A. Tags: Development & Differentiation, Metabolism, Stem Cells Articles Source Type: research