PMID- 27476977 OWN - NLM STAT- MEDLINE DCOM- 20170626 LR - 20181202 IS - 1932-7420 (Electronic) IS - 1550-4131 (Linking) VI - 24 IP - 3 DP - 2016 Sep 13 TI - Psat1-Dependent Fluctuations in alpha-Ketoglutarate Affect the Timing of ESC Differentiation. PG - 494-501 LID - S1550-4131(16)30300-X [pii] LID - 10.1016/j.cmet.2016.06.014 [doi] AB - 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 alpha-ketoglutarate (alpha-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 alpha-KG, ultimately accelerating differentiation. We found that intracellular alpha-KG declined transiently during differentiation and that its dysregulation by treatment with dimethyl-alpha-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 alpha-KG levels and determining the fate of mESCs. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Hwang, In-Young AU - Hwang IY AD - 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. FAU - Kwak, Sojung AU - Kwak S AD - 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. FAU - Lee, Sangho AU - Lee S AD - 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. FAU - Kim, Hyunsoo AU - Kim H AD - 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. FAU - Lee, Sang Eun AU - Lee SE AD - Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea. FAU - Kim, Jae-Hwan AU - Kim JH AD - 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. FAU - Kim, Young Ah AU - Kim YA AD - 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. FAU - Jeon, Yoon Kyung AU - Jeon YK AD - Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea. FAU - Chung, Doo Hyun AU - Chung DH AD - 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. FAU - Jin, Xing AU - Jin X AD - College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Republic of Korea. FAU - Park, Sunghyouk AU - Park S AD - College of Pharmacy, Natural Product Research Institute, Seoul National University, Seoul 08826, Republic of Korea. FAU - Jang, Hyonchol AU - Jang H AD - Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea. FAU - Cho, Eun-Jung AU - Cho EJ AD - College of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. FAU - Youn, Hong-Duk AU - Youn HD AD - 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. LA - eng PT - Journal Article DEP - 20160728 PL - United States TA - Cell Metab JT - Cell metabolism JID - 101233170 RN - 0 (Histones) RN - 0 (Ketoglutaric Acids) RN - 0 (Transcription Factors) RN - EC 2.6.1.- (Transaminases) RN - EC 2.6.1.52 (phosphoserine aminotransferase) SB - IM MH - Animals MH - *Cell Differentiation MH - DNA Methylation MH - Histones/metabolism MH - Intracellular Space/metabolism MH - Ketoglutaric Acids/*metabolism MH - Mice MH - Mouse Embryonic Stem Cells/*cytology/*metabolism MH - Time Factors MH - Transaminases/*metabolism MH - Transcription Factors/metabolism EDAT- 2016/08/02 06:00 MHDA- 2017/06/27 06:00 CRDT- 2016/08/02 06:00 PHST- 2016/02/14 00:00 [received] PHST- 2016/04/29 00:00 [revised] PHST- 2016/06/21 00:00 [accepted] PHST- 2016/08/02 06:00 [entrez] PHST- 2016/08/02 06:00 [pubmed] PHST- 2017/06/27 06:00 [medline] AID - S1550-4131(16)30300-X [pii] AID - 10.1016/j.cmet.2016.06.014 [doi] PST - ppublish SO - Cell Metab. 2016 Sep 13;24(3):494-501. doi: 10.1016/j.cmet.2016.06.014. Epub 2016 Jul 28.