title: Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation.
abstract: Embryonic stem cells (ESCs) undergo coordinated epigenetic and metabolic changes to differentiate properly. However, the precise mechanisms by which these alterations are fine-tuned in the early stages of differentiation have not been identified. In this study, we demonstrate that phosphoserine aminotransferase 1 (Psat1), an Oct4/Sox2/Nanog (OSN) target protein, regulates changes in α-ketoglutarate (α-KG), determining the fate of mouse ESCs (mESCs). Maintaining Psat1 levels was essential for mESC self-renewal and pluripotency. Moderate knockdown (KD) of Psat1 in mESCs lowered DNA 5'-hydroxymethylcytosine (5'-hmC) and increased histone methylation levels by downregulating permissive amounts of α-KG, ultimately accelerating differentiation. We found that intracellular α-KG declined transiently during differentiation and that its dysregulation by treatment with dimethyl-α-KG impeded differentiation. Further, by in vivo teratoma formation assay, pluripotency of Psat1 KD mESCs was impaired, especially into the ectodermal lineage. Thus, we have established how Psat1 is regulated in maintaining intracellular α-KG levels and determining the fate of mESCs.
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: In-Young
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Republic of Korea.
authors.forename: Sangho
authors.initials: S
authors.lastname: Lee
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Republic of Korea.
authors.forename: Young Ah
authors.initials: YA
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Xing
authors.initials: X
authors.lastname: Jin
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Sunghyouk
authors.initials: S
authors.lastname: Park
authors.affiliation: Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.
authors.forename: Hyonchol
authors.initials: H
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: hdyoun@snu.ac.kr.
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019175:DNA Methylation; D006657:Histones / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013997:Time Factors; D000637:Transaminases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D006657:Histones; D007656:Ketoglutaric Acids; D014157:Transcription Factors; D000637:Transaminases; C022393:phosphoserine aminotransferase