Tang Shuang, Fang Yi, Huang Gang, Xu Xiaojiang, Padilla-Banks Elizabeth, Fan Wei, Xu Qing, Sanderson Sydney M, Foley Julie F, Dowdy Scotty, McBurney Michael W, Fargo David C, Williams Carmen J, Locasale Jason W, Guan Ziqiang, Li Xiaoling
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
EMBO J. 2017 Nov 2;36(21):3175-3193. doi: 10.15252/embj.201796708. Epub 2017 Oct 11.
Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD-dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methylation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development.
甲硫氨酸代谢对于表观遗传维持、氧化还原稳态和动物发育至关重要。然而，甲硫氨酸代谢的调控仍不清楚。在此，我们提供证据表明，SIRT1作为最保守的哺乳动物NAD依赖性蛋白脱乙酰酶，在调节甲硫氨酸代谢中起关键作用，从而影响小鼠胚胎干细胞（mESCs）的维持及随后的胚胎发生。我们证明，SIRT1缺陷的mESCs对甲硫氨酸限制/耗竭诱导的分化和凋亡高度敏感，这主要是由于甲硫氨酸向S-腺苷甲硫氨酸的转化减少所致。这种减少显著降低了组蛋白的甲基化水平，导致基因表达谱发生显著改变。从机制上讲，我们发现mESCs中催化甲硫氨酸转化为S-腺苷甲硫氨酸的酶，即甲硫氨酸腺苷转移酶2a（MAT2a），受Myc和SIRT1的调控。一致地，SIRT1基因敲除胚胎的表达和组蛋白甲基化水平降低，并且对母体甲硫氨酸限制诱导的致死性敏感，而母体补充甲硫氨酸可提高SIRT1基因敲除新生小鼠的存活率。我们的研究结果揭示了一种新的甲硫氨酸代谢调控机制，并突出了甲硫氨酸代谢在SIRT1介导的mESC维持和胚胎发育中的重要性。
