Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos.
Heterogeneity in Oct4 and Sox2 Targets Biases Cell Fate in 4-Cell Mouse Embryos.
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DOI：
10.1016/j.cell.2016.01.047
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发表时间：
2016-03-24
期刊：
影响因子：
64.5
通讯作者：
Zernicka-Goetz M
中科院分区：
文献类型：
--
作者：
Goolam M;Scialdone A;Graham SJL;Macaulay IC;Jedrusik A;Hupalowska A;Voet T;Marioni JC;Zernicka-Goetz M
着床前发育的主要和基本目标是建立胚胎和胚胎外细胞命运。为了解决这一基本过程何时以及如何在哺乳动物中启动，我们对小鼠着床前发育过程中所有单个细胞的转录组进行了表征。这表明主多能性调控因子Oct4和Sox2的靶蛋白在4细胞胚胎的卵裂球之间的表达具有高度的异质性，其中Sox21表现出最异质性的表达谱之一。活细胞追踪表明，Sox21降低的细胞比多能子代产生更多的胚外细胞。一致地，Sox21的减少导致分化调节因子Cdx2的过早上调，这表明Sox21有助于保护多能性。此外，Sox21在组蛋白h3r26 -甲基化酶CARM1表达增加后升高，在CARM1抑制后降低，表明表观遗传调控的重要性。因此，我们的研究结果表明，早在4细胞阶段，异质基因表达就通过调节多能性和分化的平衡来启动细胞命运决定。Oct4和Sox2靶点如Sox21在4细胞胚胎中是高度异质的，Sox21水平的消耗导致Cdx2和胚外命运的上调，Sox21表达响应组蛋白H3R26甲基转移酶CARM1，异质基因表达启动4细胞阶段的细胞命运决定，小鼠胚胎4细胞阶段的异质基因表达有助于细胞命运决定，较低水平的Sox21促进胚外命运而不是多能性。
The major and essential objective of pre-implantation development is to establish embryonic and extra-embryonic cell fates. To address when and how this fundamental process is initiated in mammals, we characterize transcriptomes of all individual cells throughout mouse pre-implantation development. This identifies targets of master pluripotency regulators Oct4 and Sox2 as being highly heterogeneously expressed between blastomeres of the 4-cell embryo, with Sox21 showing one of the most heterogeneous expression profiles. Live-cell tracking demonstrates that cells with decreased Sox21 yield more extra-embryonic than pluripotent progeny. Consistently, decreasing Sox21 results in premature upregulation of the differentiation regulator Cdx2, suggesting that Sox21 helps safeguard pluripotency. Furthermore, Sox21 is elevated following increased expression of the histone H3R26-methylase CARM1 and is lowered following CARM1 inhibition, indicating the importance of epigenetic regulation. Therefore, our results indicate that heterogeneous gene expression, as early as the 4-cell stage, initiates cell-fate decisions by modulating the balance of pluripotency and differentiation. Oct4 and Sox2 targets such as Sox21 are highly heterogeneous in the 4-cell embryo Depleting Sox21 levels leads to upregulation of Cdx2 and extra-embryonic fate Sox21 expression responds to the histone H3R26 methyltransferase CARM1 Heterogeneous gene expression initiates cell-fate decisions at the 4-cell stage Heterogeneous gene expression in 4-cell stage in mouse embryos contributes to cell-fate decisions, with lower levels of Sox21 promoting extra-embryonic fate over pluripotency.