Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation

• Published in: Cell metabolism 2016-09, Vol.24 (3), p.494-501
• Main Authors: Hwang, In-Young, Kwak, Sojung, Lee, Sangho, Kim, Hyunsoo, Lee, Sang Eun, Kim, Jae-Hwan, Kim, Young Ah, Jeon, Yoon Kyung, Chung, Doo Hyun, Jin, Xing, Park, Sunghyouk, Jang, Hyonchol, Cho, Eun-Jung, Youn, Hong-Duk
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; DNA Methylation; Histones - metabolism; Intracellular Space - metabolism; Ketoglutaric Acids - metabolism; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Time Factors; Transaminases - metabolism; Transcription Factors - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.06.014

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. [Display omitted] •OSN-regulated Psat1 directs α-KG level in mESCs•Psat1-directed α-KG level affects epigenetic states in mESCs•mESCs undergo changes in α-KG level during differentiation•Psat1 is pivotal for maintenance of mESC self-renewal and proper differentiation Hwang et al. show that phosphoserine aminotransferase 1 (Psat1), an Oct4/Sox2/Nanog target protein, regulates changes in α-ketoglutarate (α-KG), which determine mESC pluripotency and differentiation. Psat1-regulated α-KG levels fine-tune DNA 5′-hmC and histone H3K9 tri-methylation levels in the regulatory regions of core transcription factors, thus linking metabolites to mESC fate.