Influence of Threonine Metabolism on S -Adenosylmethionine and Histone Methylation
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SAM, Histones, and Stem Cells: Mouse embryonic stem cells require threonine for growth and express large amounts of the enzyme that catalyzes the first step in threonine metabolism. To find out what is so important about threonine in these cells, Shyh-Change et al. (p. 222 , published online 1 November; see the Perspective by Sassone-Corsi ) monitored changes in metabolism by mass spectrometry in induced pluripotent stem cells. Threonine was required to maintain cellular concentrations of S-adenosylmethionine (SAM), a substrate used for protein methylation. Restriction of threonine inhibited methylation of histones, which is characteristic of chromatin in embryonic stem cells. Thus, altered metabolism of threonine and methionine in stem cells may be linked to epigenetic changes that influence genetic reprogramming and decisions of stem cells to proliferate or differentiate.
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Threonine deprivation selectively affects H3K4me2 and H3K4me3 but not H3K4me1, H3K9me3, H3K27me3, H3K36me3, or H3K79me3 marks.
“These impediments were selective; threonine deprivation had no effect on the deposition of H3K4me1, H3K9me3, H3K27me3, H3K36me3, or H3K79me3 marks on histone tails.”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shyh-Chang et al., 2013
H3K4me2 and H3K4me3 marks lost upon threonine deprivation are part of a bivalent epigenetic state important for keeping developmental transcription factor genes repressed or poised for induction during embryogenesis.
“The H3K4me2 and H3K3me3 marks that disappear when mouse ESCs are deprived of threonine (Shyh-Chang et al., 2013) are part of a “bivalent” epigenetic state believed to be uniquely important for keeping the chromatin structure of genes encoding developmentally important transcription factors in a properly repressed/poised state for subsequent induction as a function of embryogenesis (Bernstein et al”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shyh-Chang et al., 2013
TDH-mediated threonine catabolism may be important for maintaining high SAM levels in mouse ESCs.
“More recent work on mouse ESCs has led to the conclusion that TDH-mediated catabolism of threonine might also be important for maintaining high levels of SAM (Shyh-Chang et al., 2013).”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shyh-Chang et al., 2013
Threonine restriction dramatically impedes deposition of H3K4me2 and H3K4me3 marks on chromatin.
“Intriguingly, threonine restriction was observed to dramatically impede deposition of the H3K4me2 and H3K4me3 marks on chromatin.”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Shyh-Chang et al., 2013
Histone and DNA methylation is sensitive to alterations in SAM levels.
“A number of recent reports demonstrate that histone and DNA methylation is sensitive to alterations in SAM levels (Chiang et al., 2009; Shyh-Chang et al., 2013; Towbin et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Shyh-Chang et al., 2013
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References 25 · Cited by 638
- Authors
- Shyh-Chang, N., Locasale, J. W., Lyssiotis, C. A., Zheng, Y., Teo, R. Y., Ratanasirintrawoot, S., Zhang, J., Onder, T., Unternaehrer, J. J., Zhu, H., Asara, J. M., Daley, G. Q., & Cantley, L. C.
- Affiliations
- 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.
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Daley, George Q.
- Cantley, Lewis C.
- ORCID
- Venue
- Science
- Published
- 2013-01-11
- Volume
- 339
- Issue
- 6116
- Pages
- 222-226
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3652341
- OpenAlex
- W2056077438
- Cited by
- 638
- References
- 25
- Citations by year
- 2026: 31 · 2025: 32 · 2024: 35 · 2023: 42 · 2022: 59 · 2021: 52 · 2020: 47 · 2019: 53 · 2018: 46 · 2017: 55 · 2016: 60 · 2015: 48 · 2014: 36 · 2013: 38 · 2012: 4
- FWCI
- 16.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (4R00CA168997-02, RC2HL102815, U01 HL100001, R01 GM56203)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- threonine metabolism, S-adenosylmethionine, histone methylation, H3K4 trimethylation, mouse embryonic stem cells, pluripotency, threonine dehydrogenase, glycine synthesis, acetyl-CoA, stem cell differentiation, isotopic labeling
- MeSH terms
- Acetyl Coenzyme A, Alcohol Oxidoreductases, Animals, Cell Differentiation, Cells, Cultured, Culture Media, Fibroblasts, Glycine, Histones, Methylation, S-Adenosylmethionine, Threonine, Transcription Factors, Pluripotent Stem Cells, Epigenesis, Genetic, Mice, Embryonic Stem Cells, Metabolic Networks and Pathways, Induced Pluripotent Stem Cells, Cellular Reprogramming
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