Concise Review: Energy Metabolites: Key Mediators of the Epigenetic State of Pluripotency

Abstract

Recent studies suggest that the metabolic network is an important part of the molecular circuitry that underlies pluripotency. Of the metabolic pathways that were implicated in the pluripotency balance, "energy" metabolism is particularly notable. Its mechanism of action on pluripotency-regulating genes has been partially elucidated when three metabolites, namely acetate, S-adenosylmethionine, and O-linked b-N-acetylglucosamine were recently shown to link cytosolic signals to pluripotent gene expression. The cytosolic levels of these metabolites are the result of environmental perturbations, making them sensitive messengers, which are assumed to diffuse through the nuclear pores, being small molecules. Recent work also suggests that the modulation of the levels of these metabolites in pluripotent cells controls the balance between pluripotency and early commitment via epigenetic modifications. Here, we review recent studies that link metabolism and pluripotency via epigenetic modifications that occur through these three metabolites.

Metabolic Reprogramming of Stem Cell Epigenetics

“…Furthermore, HSCs from PDK2 −/− PDK4 −/− mice exhibited increased Oxphos activity and expression of the senescent marker p16 (Takubo et al, 2013). These results differ from those obtained in a more recent study where ESCs cultured in the presence of dichloroacetic acid (DCA, an inhibitor of pyruvate dehydrogenase kinases, PDK) were better able to maintain pluripotency (Moussaieff et al, 2015a). Thus, the process of metabolic reprogramming is likely different in different populations of stem cells.…”

“…Regulation of histone acetylation by cytoplasmic acetyl-CoA also seems to be an important determinant of the PSC state. High glycolytic rates drive this process and have recently been shown to be critical for stem cell maintenance (Moussaieff et al, 2015a). Consistent with this, glycolytic rates, acetyl-CoA levels and global histone acetylation decline during early differentiation.…”

“…These authors also found that targeted deletion of Ppard (a transcription factor intricately linked to the process of FAO) in HSC led to precocious exit from quiescence (Ito et al, 2012). Therefore, it is essential that future studies investigate the role of FAO-derived acetyl-CoA and oxidative phosphorylation in the maintenance of the HSC pool, particularly as acetyl-CoA has been linked to pluripotency in ESCs (Moussaieff et al, 2015a). …”

“…Additionally, the metabolite balance of both stem and differentiated cells has been found to directly influence the epigenome through post-translational modifications of histones, DNA and transcription factors (Carey et al, 2015; Moussaieff et al, 2015a; Ryall et al, 2015; Shiraki et al, 2014; Wellen et al, 2009). These findings indicate that cellular metabolism is not a passive player in the process of stem cell lineage commitment, but rather suggest that changes in metabolism regulate many of the important cell fate decisions made by stem cells.…”

MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

“…One idea that has received significant attention has been the impact of metabolic changes on epigenetic modifications that can potentially regulate global or specific patterns of gene regulation to elicit cell fate changes (Moussaieff et al, 2015a; Shyh-Chang and Daley, 2015). Here, high glycolytic flux elevates levels of acetyl CoA that contributes to increased histone acetylation and, as a consequence, maintenance of pluripotency.…”