O-GlcNAcylation regulates the methionine cycle to promote pluripotency of stem cells
O-GlcNAcylation regulates the methionine cycle to promote pluripotency of stem cells
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O-GlcNAcylation 调节蛋氨酸循环促进干细胞的多能性
DOI：
10.1073/pnas.1915582117
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yi Wen
中科院分区：
文献类型：
--
作者：
Zhu Qiang;Cheng Xuejun;Cheng Yaxian;Chen Junchen;Xu Huan;Gao Yuntao;Duan Xiaotao;Ji Junfeng;Li Xuekun;Yi Wen
胚胎干细胞的增殖和分化能力受多种因素的影响。其中，必需氨基酸蛋氨酸的代谢被认为是非常重要的。然而，蛋氨酸代谢的详细调控机制以及代谢如何影响干细胞命运仍然知之甚少。在这项研究中，我们确定了AHCY，一种参与甲硫氨酸代谢的重要酶，作为维持干细胞身份的关键参与者。AHCY被一种单糖N-乙酰葡萄糖胺动态修饰，它响应环境信号调节其活性，并进一步影响干细胞的增殖和分化。我们的发现扩展了我们目前对糖基化在控制细胞命运决定中的作用的理解。甲硫氨酸代谢对于维持胚胎干细胞（ESC）和诱导多能干细胞（iPSC）的多能性至关重要。然而，关于蛋氨酸循环的调节以维持ESC多能性知之甚少。在这里，我们表明，腺苷高半胱氨酸酶（AHCY），蛋氨酸循环中的一个重要酶，是至关重要的小鼠胚胎干细胞（mESCs）的维持和分化。我们发现，胚胎干细胞表现出高水平的甲硫氨酸代谢，而减少甲硫氨酸代谢通过消耗AHCY促进胚胎干细胞分化成三个胚层。AHCY在分化后被O-连接的β-N-乙酰葡糖胺糖（O-GlcNAc化）修饰，在分化后迅速去除。AHCY上苏氨酸136的O-GlcNAc酰化增加其活性，并且对于维持组蛋白H3赖氨酸4（H3 K4 me 3）的三甲基化以维持mESC多能性是重要的。阻断AHCY的糖基化可降低S-腺苷甲硫氨酸与S-腺苷高半胱氨酸（SAM/SAH）的比率，降低H3 K4 me 3的水平，并使mESC分化平衡。此外，阻断AHCY的糖基化减少体细胞重编程。因此，我们的研究结果揭示了AHCY和O-糖基化在调节ESC多能性和分化中的关键作用。
Significance The ability of embryonic stem cells to proliferate and differentiate is influenced by a number of factors. Among them, the metabolism of methionine, an essential amino acid, is considered highly important. However, the detailed regulatory mechanism of methionine metabolism and how the metabolism influences the stem cell fate still remain poorly understood. In this study, we identified AHCY, an important enzyme involved in the methionine metabolism, as a key player in the maintenance of stem cell identity. AHCY is dynamically modified by a single sugar N-acetylglucosamine, which responds to environmental cues to regulate its activity, and further influences stem cell proliferation and differentiation. Our finding expands our current understanding of the role of glycosylation in controlling cell fate decisions. Methionine metabolism is critical for the maintenance of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) pluripotency. However, little is known about the regulation of the methionine cycle to sustain ESC pluripotency. Here, we show that adenosylhomocysteinase (AHCY), an important enzyme in the methionine cycle, is critical for the maintenance and differentiation of mouse embryonic stem cells (mESCs). We show that mESCs exhibit high levels of methionine metabolism, whereas decreasing methionine metabolism via depletion of AHCY promotes mESCs to differentiate into the three germ layers. AHCY is posttranslationally modified with an O-linked β-N-acetylglucosamine sugar (O-GlcNAcylation), which is rapidly removed upon differentiation. O-GlcNAcylation of threonine 136 on AHCY increases its activity and is important for the maintenance of trimethylation of histone H3 lysine 4 (H3K4me3) to sustain mESC pluripotency. Blocking glycosylation of AHCY decreases the ratio of S-adenosylmethionine versus S-adenosylhomocysteine (SAM/SAH), reduces the level of H3K4me3, and poises mESC for differentiation. In addition, blocking glycosylation of AHCY reduces somatic cell reprogramming. Thus, our findings reveal a critical role of AHCY and a mechanistic understanding of O-glycosylation in regulating ESC pluripotency and differentiation.