Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetyl Coenzyme A / metabolism
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Alcohol Oxidoreductases / metabolism
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Animals
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Cell Differentiation
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Cells, Cultured
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Cellular Reprogramming
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Culture Media
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Embryonic Stem Cells / cytology*
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Embryonic Stem Cells / metabolism*
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Epigenesis, Genetic
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Glycine / metabolism
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Histones / metabolism*
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / metabolism*
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Metabolic Networks and Pathways
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Methylation
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Mice
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / metabolism*
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S-Adenosylmethionine / metabolism*
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Threonine / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Culture Media
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Histones
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Transcription Factors
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Threonine
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Acetyl Coenzyme A
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S-Adenosylmethionine
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Alcohol Oxidoreductases
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L-threonine 3-dehydrogenase
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Glycine