Influence of Threonine Metabolism on S-Adenosylmethionine and Histone Methylation

Stem Cell Transplantation Program, Division of Pediatric Hematology and Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.
Science (Impact Factor: 33.61). 01/2013; 339(6116):222-226. DOI: 10.1126/science.1226603


Threonine is the only amino acid critically required for the pluripotency of mouse embryonic stem cells (mESCs), but the detailed
mechanism remains unclear. We found that threonine and S-adenosylmethionine (SAM) metabolism are coupled in pluripotent stem cells, resulting in regulation of histone methylation.
Isotope labeling of mESCs revealed that threonine provides a substantial fraction of both the cellular glycine and the acetyl–coenzyme
A (CoA) needed for SAM synthesis. Depletion of threonine from the culture medium or threonine dehydrogenase (Tdh) from mESCs
decreased accumulation of SAM and decreased trimethylation of histone H3 lysine 4 (H3K4me3), leading to slowed growth and
increased differentiation. Thus, abundance of SAM appears to influence H3K4me3, providing a possible mechanism by which modulation
of a metabolic pathway might influence stem cell fate.

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    • "Given these previous findings, we hypothesized that there exists a direct mechanism whereby the status of one-carbon metabolism could alter the concentrations of SAM and SAH to confer, through their interaction with methyltransferases, the output of a defined methylation state. We focused on histones because key methylation modifications on their tails, such as trimethylation at lysine 4, are known to be required for the maintenance of defined cellular states (Benayoun et al., 2014; Ruthenburg et al., 2007) and have been shown to be modulated by metabolism (Shiraki et al., 2014; Shyh-Chang et al., 2013). We provide evidence in cells and mice that both SAM levels and the SAM/SAH ratio can be quantitatively tuned through changes in the metabolic flux of the methionine cycle to affect a critical component of chromatin status. "
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    ABSTRACT: One-carbon metabolism is a metabolic network that integrates nutrient status from the environment to yield multiple biological functions. The folate and methionine cycles generate S-adenosylmethionine (SAM), which is the universal methyl donor for methylation reactions, including histone and DNA methylation. Histone methylation is a crucial part of the epigenetic code and plays diverse roles in the establishment of chromatin states that mediate the regulation of gene expression. The activities of histone methyltransferases (HMTs) are dependent on intracellular levels of SAM, which fluctuate based on cellular nutrient availability, providing a link between cell metabolism and histone methylation. Here we discuss the biochemical properties of HMTs, their role in gene regulation, and the connection to cellular metabolism. Our emphasis is on understanding the specificity of this intriguing link.
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    • "understanding precisely how environmental factors like diet can, for example, signal into our cells' nuclei to regulate gene expression and chromatin structure. Dietary intake of the amino acid threonine affects cellular levels of the methyl donor S-adenosylmethionine, which in turn promotes histone methylation and regulates stem cell function [2]. Lipidburning states, such as fasting, increase both acetyl-CoA production and levels of histone acetylation [3]. "
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    ABSTRACT: The ketone body β-hydroxybutyrate (βOHB) is a convenient carrier of energy from adipocytes to peripheral tissues during fasting or exercise. However, βOHB is more than just a metabolite, having important cellular signaling roles as well. βOHB is an endogenous inhibitor of histone deacetylases (HDACs) and a ligand for at least two cell surface receptors. In addition, the downstream products of βOHB metabolism including acetyl-CoA, succinyl-CoA, and NAD+ (nicotinamide adenine dinucleotide) themselves have signaling activities. These regulatory functions of βOHB serve to link the outside environment to cellular function and gene expression, and have important implications for the pathogenesis and treatment of metabolic diseases including type 2 diabetes.
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    • "SAM functions as a major methyl donor in methyl transfer reactions, such as methylation of histone H3 K4, K9, K27, and K36 and DNA methylation. A study in mouse ESCs demonstrated that SAM reduction decreased H3K4me3 (Shyh-Chang et al., 2013), but the effect of SAM reduction on epigenetic modifications of human ESCs/iPSCs is unknown. We thus examined the impact of Met deprivation on histone (Figures 5A and 5B) and DNA methylation (Figure 5C). "
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    ABSTRACT: Mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are in a high-flux metabolic state, with a high dependence on threonine catabolism. However, little is known regarding amino acid metabolism in human ESCs/iPSCs. We show that human ESCs/iPSCs require high amounts of methionine (Met) and express high levels of enzymes involved in Met metabolism. Met deprivation results in a rapid decrease in intracellular S-adenosylmethionine (SAM), triggering the activation of p53-p38 signaling, reducing NANOG expression, and poising human iPSC/ESCs for differentiation, follow by potentiated differentiation into all three germ layers. However, when exposed to prolonged Met deprivation, the cells undergo apoptosis. We also show that human ESCs/iPSCs have regulatory systems to maintain constant intracellular Met and SAM levels. Our findings show that SAM is a key regulator for maintaining undifferentiated pluripotent stem cells and regulating their differentiation.
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