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

• DOI: 10.1016/j.cmet.2016.06.014
• Publication Date: 2016-07-29T18:27:01Z
• Authors: In-Young Hwang; Sojung Kwak; Sangho Lee; Hyunsoo Kim; Sang Eun Lee; Jae-Hwan Kim; Young Ah Kim; Yoon Kyung Jeon; Doo Hyun Chung; Xing Jin; Sunghyouk Park; Hyonchol Jang; Eun-Jung Cho; Hong-Duk Youn
• Keywords: 0303 health sciences; Time Factors; Intracellular Space; Cell Differentiation; Mouse Embryonic Stem Cells; DNA Methylation; Histones; Mice; 03 medical and health sciences; Animals; Ketoglutaric Acids; Transaminases; Transcription Factors

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.