Influence of Threonine Metabolism on S-Adenosylmethionine and Histone Methylation

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Science  01 Nov 2012:
DOI: 10.1126/science.1226603

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Threonine is the only amino acid critically required for the pluripotency of mouse embryonic stem cells (mESCs), but by an unknown mechanism. We demonstrate that threonine (Thr) and S-adenosylmethionine (SAM) metabolism are coupled in pluripotent stem cells, resulting in regulation of histone methylation. Isotope labeling of mESCs revealed that Thr provides a significant fraction of both the cellular glycine and the acetyl-CoA needed for SAM synthesis. Depletion of Thr from the culture medium or threonine dehydrogenase from mESCs decreased accumulation of SAM and decreased tri-methylation 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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