Histone arginine methylation regulates pluripotency in the early mouse embryo.
Histone arginine methylation regulates pluripotency in the early mouse embryo.
复制标题
组蛋白精氨酸甲基化调节早期小鼠胚胎中的多能性。
DOI：
10.1038/nature05458
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发表时间：
2007-01-11
期刊：
影响因子：
64.8
通讯作者：
Zernicka-Goetz, Magdalena
中科院分区：
文献类型：
--
作者：
Torres-Padilla, Maria-Elena;Parfitt, David-Emlyn;Kouzarides, Tony;Zernicka-Goetz, Magdalena
人们普遍认为，哺乳动物胚胎开始发育时，所有细胞都是相同的，只有当细胞内外形成时，细胞之间才会出现差异。然而，最近的研究结果表明，小鼠胚胎中的细胞在4细胞阶段就已经在发育命运和效力上有所不同。这种差异取决于产生它们的解理分裂的方向和顺序。由于表观遗传标记被认为参与维持多能性，我们认为这种发育特性可能通过表观遗传机制实现。在这里，我们发现组蛋白H3的修饰，通过特定精氨酸残基的甲基化，与细胞的命运和效力相关。特定精氨酸的H3甲基化水平在4细胞卵裂球中最高，这将有助于ICM和极地滋养外胚层的形成，并在嵌合体中结合在一起进行完全发育。H3的精氨酸甲基化在后代对壁养外胚层贡献更多的细胞中是最小的，并且在嵌合体中结合时显示出发育受损。这表明高水平的H3精氨酸甲基化使卵裂球易于形成ICM的多能细胞。我们通过在单个卵裂球中过表达h3特异性精氨酸甲基转移酶CARM1来证实这一预测，并表明这将它们的后代引导到ICM，并导致Nanog和Sox2的显著上调。因此，我们的研究结果确定了特定的组蛋白修饰是已知最早的表观遗传标记，有助于ICM的发展，并表明表观遗传信息的操纵影响细胞命运的决定。
It has been generally accepted that the mammalian embryo starts its development with all cells identical and only when inside and outside cells form do differences between cells first emerge. However, recent findings show that cells in the mouse embryo can differ in their developmental fate and potency already by the 4-cell-stage. Such differences depend on the orientation and order of the cleavage divisions that generated them. Since epigenetic marks are suggested to be involved in sustaining pluripotency, we considered that such developmental properties might be achieved through epigenetic mechanisms. Here, we show that modification of histone H3, through methylation of specific arginine residues, correlates with cell fate and potency. Levels of H3 methylation at specific arginines are maximal in 4-cell blastomeres that will contribute to the ICM and polar trophectoderm and undertake full development when combined together in chimeras. Arginine methylation of H3 is minimal in cells whose progeny contributes more to the mural trophectoderm and that show compromised development when combined in chimeras. This suggests that higher levels of H3 arginine methylation predispose blastomeres to contribute to the pluripotent cells of the ICM. We confirm this prediction by overexpressing the H3-specific arginine methyltransferase, CARM1, in individual blastomeres and show this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2. Thus, our results identify specific histone modifications as the earliest known epigenetic marker contributing to development of ICM and show that manipulation of epigenetic information influences cell fate determination.
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