Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation
Psat1-Dependent Fluctuations in α-Ketoglutarate Affect the Timing of ESC Differentiation
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DOI：
10.1016/j.cmet.2016.06.014
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发表时间：
2016-09-13
期刊：
影响因子：
29
通讯作者：
Youn, Hong-Duk
中科院分区：
文献类型：
--
作者：
Hwang, In-Young;Kwak, Sojung;Youn, Hong-Duk
胚胎干细胞（ESC）经历协调的表观遗传和代谢变化以适当分化。然而，这些变化在分化早期阶段被微调的确切机制尚未确定。在这项研究中，我们证明了磷酸丝氨酸氨基转移酶1（Psat 1），Oct 4/Sox 2/Nanog（OSN）靶蛋白，调节α-酮戊二酸（alpha-KG）的变化，决定小鼠胚胎干细胞（mESC）的命运。维持Psat 1水平对mESC自我更新和多能性至关重要。在mESC中适度敲低（KD）Psat 1降低DNA 50-羟甲基胞嘧啶（5 '-hmC），并通过下调允许量的α-KG增加组蛋白甲基化水平，最终加速分化。我们发现，细胞内α-KG下降短暂分化过程中，其失调与二甲基-α-KG治疗阻碍分化。此外，通过体内畸胎瘤形成测定，Psat 1 KD mESC的多能性受损，特别是进入外胚层谱系。因此，我们已经确定了Psat 1是如何在维持细胞内α-KG水平和决定mESC的命运方面受到调节的。
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 50-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.