MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JQ, Scotland, UK.
Hum Genet. 2011 Aug;130(2):255-64. doi: 10.1007/s00439-011-0998-5. Epub 2011 May 5.
X-inactivation, the molecular mechanism enabling dosage compensation in mammals, is tightly controlled during mouse early embryogenesis. In the morula, X-inactivation is imprinted with exclusive silencing of the paternally inherited X-chromosome. In contrast, in the post-implantation epiblast, X-inactivation affects randomly either the paternal or the maternal X-chromosome. The transition from imprinted to random X-inactivation takes place in the inner cell mass (ICM) of the blastocyst from which embryonic stem (ES) cells are derived. The trigger of X-inactivation, Xist, is specifically downregulated in the pluripotent cells of the ICM, thereby ensuring the reactivation of the inactive paternal X-chromosome and the transient presence of two active X-chromosomes. Moreover, Tsix, a critical cis-repressor of Xist, is upregulated in the ICM and in ES cells where it imposes a particular chromatin state at the Xist promoter that ensures the establishment of random X-inactivation upon differentiation. Recently, we have shown that key transcription factors supporting pluripotency directly repress Xist and activate Tsix and thus couple Xist/Tsix control to pluripotency. In this manuscript, we report that Rnf12, a third X-linked gene critical for the regulation of X-inactivation, is under the control of Nanog, Oct4 and Sox2, the three factors lying at the heart of the pluripotency network. We conclude that in mouse ES cells the pluripotency-associated machinery exerts an exhaustive control of X-inactivation by taking over the regulation of all three major regulators of X-inactivation: Xist, Tsix, and Rnf12.
X 染色体失活是哺乳动物中实现剂量补偿的分子机制，在小鼠早期胚胎发生过程中受到严格控制。在桑葚胚中，X 染色体失活被印记为父系 X 染色体的特异性沉默。相比之下，在植入后的胚胎外胚层中，X 染色体失活随机影响父系或母系 X 染色体。从印记到随机 X 染色体失活的转变发生在从其衍生出胚胎干细胞（ES 细胞）的囊胚内细胞团（ICM）中。X 染色体失活的触发因子 Xist 在 ICM 的多能细胞中特异性下调，从而确保失活的父系 X 染色体的重新激活和两个活性 X 染色体的短暂存在。此外，Tsix 是 Xist 的关键顺式抑制因子，在 ICM 和 ES 细胞中上调，在那里它在 Xist 启动子处施加特定的染色质状态，以确保在分化时建立随机 X 染色体失活。最近，我们已经表明，支持多能性的关键转录因子直接抑制 Xist 并激活 Tsix，从而将 Xist/Tsix 控制与多能性联系起来。在本文中，我们报告称，Rnf12 是第三个对 X 染色体失活调节至关重要的 X 连锁基因，受 Nanog、Oct4 和 Sox2 的控制，这三个因子位于多能性网络的核心。我们得出的结论是，在小鼠 ES 细胞中，多能相关机制通过接管所有三个主要的 X 染色体失活调节剂：Xist、Tsix 和 Rnf12 的调节，对 X 染色体失活进行了详尽的控制。
