Influence of Threonine Metabolism on S-Adenosylmethionine and Histone Methylation

Ng Shyh-Chang1,2,3,4,5,6, Jason W. Locasale5,6,*, Costas A. Lyssiotis5,6, Yuxiang Zheng5,6, Ren Yi Teo1,Sutheera Ratanasirintrawoot1,2,3, Jin Zhang1,2,3, Tamer Onder1,2,3, Juli J. Unternaehrer1,2,3, Hao Zhu1,2,3,John M. Asara5, George Q. Daley1,2,3,4,†, Lewis C. Cantley5,6,†

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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