Metaboloepigenetic Regulation of Pluripotent Stem Cells

Figure 1

Metabolic regulation of the pluripotent epigenetic landscape. Pluripotent stem cells are characterized by spherical, electron-poor mitochondria, which contain few cristae. These cells rely heavily on glycolysis for ATP generation (thick black arrows), resulting in significant lactate production through the conversion of pyruvate to lactate by lactate dehydrogenase (LDH). Consequently, oxidative phosphorylation (OXPHOS) contributes minimally to total ATP. Glucose metabolized by the pentose phosphate pathway (PPP) generates the ribose moieties required for DNA and RNA synthesis and the NADPH required for the biosynthesis of lipids and other complex molecules. Intermediate metabolites generated via metabolic pathways act as cofactors for epigenetic modifying enzymes. Threonine and methionine metabolism is required for S-adenosyl methionine (SAM) generation via the folate and SAM cycles in mouse and human pluripotent stem cells, respectively [60, 61]. SAM acts as a methyl donor for histone methyltransferases (HMT) as well as DNA methyltransferases. Demethylation of SAM yields S-adenosylhomocysteine (SAH), which is, in turn, hydrolyzed to homocysteine. Transfer of a methyl group to homocysteine from the folate pathway regenerates methionine. Acetyl coenzyme A (Acetyl-CoA) acts as a cofactor for histone acetyltransferases (HAT). Acetyl-CoA, generated from glucose derived pyruvate, modulates human pluripotent stem cell histone acetylation [76], although pyruvate dehydrogenase kinase (PDK) activity may limit the conversion of pyruvate to acetyl-CoA [79]. Similarly, uncoupling protein 2 (UCP2) functions to shunt pyruvate away from the tricarboxylic acid (TCA) cycle, facilitating lactate production [79]. Acetyl-CoA can also be generated from threonine catabolism [62]. Alpha-ketoglutarate (KG) [65] or supplementation with vitamin C in culture [122] reduces histone and DNA methylation in human pluripotent stem cells, respectively. These metabolites modulate histone and DNA demethylation reactions catalyzed by Jumonji (JMJ) and Ten-Eleven Translocation (TET) demethylases, respectively [101]. The hexosamine biosynthetic pathway (HBP) is an alternative route of glucose utilization that generates the coenzyme UDP-GlcNAc, which together with O-linked N-acetylglucosamine transferase (OGT) leads to histone O-GlcNAcylation [82]. Flux through glycolysis and oxidative phosphorylation determines the NAD⁺ : NADH ratio, known to regulate the activity of the NAD⁺-dependent histone deacetylases sirtuins (SIRT; [90]). In addition, a proline-dependent mechanism of epigenetic regulation has been reported in pluripotent stem cells [74]; however, it is unclear how the metabolism of proline interacts with these pathways. Metabolic regulators of chromatin-modifying enzymes are highlighted in red.