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

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.

SUBMITTER: Tischler J

PROVIDER: S-EPMC6315289 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Tischler Julia J Gruhn Wolfram H WH Reid John J Allgeyer Edward E Buettner Florian F Marr Carsten C Theis Fabian F Simons Ben D BD Wernisch Lorenz L Surani M Azim MA

The EMBO journal 20180926 1

An intricate link is becoming apparent between metabolism and cellular identities. Here, we explore the basis for such a link in an <i>in vitro</i> 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 cyc ...[more]

PMID: 30257965

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Project description:The tumour suppressor TP53 is mutated in the majority of human cancers, and in over 70% of pancreatic ductal adenocarcinoma (PDAC)1,2. Wild-type p53 accumulates in response to cellular stress, and regulates gene expression to alter cell fate and prevent tumour development2. Wild-type p53 is also known to modulate cellular metabolic pathways3, although p53-dependent metabolic alterations that constrain cancer progression remain poorly understood. Here we find that p53 remodels cancer-cell metabolism to enforce changes in chromatin and gene expression that favour a premalignant cell fate. Restoring p53 function in cancer cells derived from KRAS-mutant mouse models of PDAC leads to the accumulation of ?-ketoglutarate (?KG, also known as 2-oxoglutarate), a metabolite that also serves as an obligate substrate for a subset of chromatin-modifying enzymes. p53 induces transcriptional programs that are characteristic of premalignant differentiation, and this effect can be partially recapitulated by the addition of cell-permeable ?KG. Increased levels of the ?KG-dependent chromatin modification 5-hydroxymethylcytosine (5hmC) accompany the tumour-cell differentiation that is triggered by p53, whereas decreased 5hmC characterizes the transition from premalignant to de-differentiated malignant lesions that is associated with mutations in Trp53. Enforcing the accumulation of ?KG in p53-deficient PDAC cells through the inhibition of oxoglutarate dehydrogenase-an enzyme of the tricarboxylic acid cycle-specifically results in increased 5hmC, tumour-cell differentiation and decreased tumour-cell fitness. Conversely, increasing the intracellular levels of succinate (a competitive inhibitor of ?KG-dependent dioxygenases) blunts p53-driven tumour suppression. These data suggest that ?KG is an effector of p53-mediated tumour suppression, and that the accumulation of ?KG in p53-deficient tumours can drive tumour-cell differentiation and antagonize malignant progression.

Dataset Information

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

Publications

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

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