Transient methionine deprivation triggers histone modification and potentiated differentiation of induced pluripotent stem cells
Transient methionine deprivation triggers histone modification and potentiated differentiation of induced pluripotent stem cells
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短暂的蛋氨酸剥夺触发组蛋白修饰和诱导多能干细胞的强化分化
DOI：
10.1093/stmcls/sxac082
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发表时间：
2023
期刊：
影响因子：
5.2
通讯作者：
Kume S.
中科院分区：
文献类型：
--
作者：
Ozawa H.;Kambe A;Hibi K;Murakami S;Oikawa A;Handa T;Fujiki K;Nakato R;Shirahige K;Kimura H;Shiraki N;Kume S.
人类诱导多能干细胞（iPSC）需要高水平的甲硫氨酸（Met）。Met剥夺导致细胞内S-腺苷甲硫氨酸（SAM）的快速减少，使人iPSC分化并导致未分化细胞的凋亡。甲硫氨酸剥夺触发快速代谢变化，包括SAM，随后是可逆的表观遗传修饰。在这里，我们表明，短期甲硫氨酸剥夺损害多能性网络通过表观遗传修饰在三维悬浮培养。与其他组蛋白修饰相比，组蛋白H3上赖氨酸4的三甲基化（H3 K4 me 3）受到极大影响。短期Met剥夺特异性影响基因的转录起始位点（TSS）区域，例如参与转化生长因子β途径和胆固醇生物合成过程的基因，以及关键的多能基因，如NANOGandPOU 5 F1。这些基因的表达水平降低，与H3 K4 me 3标记的丢失相关。在分化时，Met剥夺触发各种谱系特异性基因的上调，包括关键的定形内胚层基因，如GATA 6。在分化时，许多内胚层基因中发生H3 K27 me 3的丢失，从二价转换为单价（H3 K4 me 3）状态。总之，Met代谢维持了具有组蛋白标记的多能网络，并且它们的丢失增强了分化。
Human induced pluripotent stem cells (iPSCs) require high levels of methionine (Met). Met deprivation results in a rapid decrease in intracellular S-adenosyl-methionine (SAM), poising human iPSCs for differentiation and leading to the apoptosis of undifferentiated cells. Met deprivation triggers rapid metabolic changes, including SAM, followed by reversible epigenetic modifications. Here, we show that short-term Met deprivation impairs the pluripotency network through epigenetic modification in a 3D suspension culture. The trimethylation of lysine 4 on histone H3 (H3K4me3) was drastically affected compared with other histone modifications. Short-term Met deprivation specifically affects the transcription start site (TSS) region of genes, such as those involved in the transforming growth factor β pathway and cholesterol biosynthetic process, besides key pluripotent genes such asNANOGandPOU5F1. The expression levels of these genes decreased, correlating with the loss of H3K4me3 marks. Upon differentiation, Met deprivation triggers the upregulation of various lineage-specific genes, including key definitive endoderm genes, such asGATA6. Upon differentiation, loss of H3K27me3 occurs in many endodermal genes, switching from a bivalent to a monovalent (H3K4me3) state. In conclusion, Met metabolism maintains the pluripotent network with histone marks, and their loss potentiates differentiation.