title: Influence of threonine metabolism on S-adenosylmethionine and histone methylation.
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.
authors.affiliation: 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.
authors.forename: Ng
authors.initials: N
authors.lastname: Shyh-Chang
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Ren Yi
authors.initials: RY
authors.lastname: Teo
authors.forename: Sutheera
authors.initials: S
authors.lastname: Ratanasirintrawoot
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Tamer
authors.initials: T
authors.lastname: Onder
authors.forename: Juli J
authors.initials: JJ
authors.lastname: Unternaehrer
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D003470:Culture Media; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008745:Methylation; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D003470:Culture Media; D006657:Histones; D014157:Transcription Factors; D013912:Threonine; D000105:Acetyl Coenzyme A; D012436:S-Adenosylmethionine; D000429:Alcohol Oxidoreductases; C023159:L-threonine 3-dehydrogenase; D005998:Glycine