Goolam Mubeen, Scialdone Antonio, Graham Sarah J L, Macaulay Iain C, Jedrusik Agnieszka, Hupalowska Anna, Voet Thierry, Marioni John C, Zernicka-Goetz Magdalena
Department of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI), Wellcome Genome Campus, Cambridge CB10 1SD, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
Cell. 2016 Mar 24;165(1):61-74. doi: 10.1016/j.cell.2016.01.047.
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.
植入前发育的主要和基本目标是确立胚胎细胞和胚外细胞的命运。为了探究这一基本过程在哺乳动物中何时以及如何启动，我们对小鼠植入前发育全过程中所有单个细胞的转录组进行了特征分析。这表明，全能性主调控因子Oct4和Sox2的靶标在4细胞胚胎的卵裂球之间呈现高度异质性表达，其中Sox21的表达谱最为异质。活细胞追踪显示，Sox21表达降低的细胞产生的胚外后代比多能后代更多。同样，降低Sox21会导致分化调控因子Cdx2过早上调，这表明Sox21有助于维持多能性。此外，组蛋白H3R26甲基转移酶CARM1表达增加后Sox21升高，CARM抑制后Sox21降低，这表明表观遗传调控的重要性。因此，我们的结果表明，早在4细胞阶段的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。
