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: 31.48). 01/2013; 339(6116):222-226. DOI: 10.1126/science.1226603

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.

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May 21, 2014