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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    • "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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    • "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.
    Cell metabolism 04/2014; 19(5). DOI:10.1016/j.cmet.2014.03.017 · 17.57 Impact Factor
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    • "In a third example, a genome-wide screen revealed unexpectedly that threonine metabolism is required to buffer a deficiency of dNTP biosynthesis, through augmenting provision of metabolic intermediates to overcome inhibition of a key enzyme, ribonucleotide reductase [20]. Although threonine biosynthesis does not occur in multicellular eukaryotes, it was nevertheless shown that threonine catabolism is required in a developmentally-regulated way for DNA synthesis in mouse embryonic stem cells [70], and also for maintenance of stem cell chromatin state through S-adenosyl-methionine metabolism and histone methylation [71]. Our study, together with these and other models indicate the power and utility of yeast genetic screens for generating useful new hypotheses about the role of gene interaction in phenotypic diversity, including human disease [5,72]. "
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