The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation
The Trithorax group protein Ash2l and Saf-A are recruited to the inactive X chromosome at the onset of stable X inactivation
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DOI：
10.1242/dev.035956
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发表时间：
2010-03-15
期刊：
影响因子：
4.6
通讯作者：
Wutz, Anton
中科院分区：
文献类型：
--
作者：
Pullirsch, Dieter;Haertel, Renate;Wutz, Anton
哺乳动物通过沉默两条雌性X染色体中的一条来补偿两性之间的X染色体基因剂量。X失活是在早期胚胎中启动的，需要非编码的Xist RNA，它包含不活跃的X染色体(XI)并触发其沉默。在分化的细胞中，几个因子，包括组蛋白变异体宏H_2A和支架附着因子SAF-A被招募到XI并维持其抑制。因此，在雌性体细胞中，XI保持稳定的沉默，而不受Xist的影响。在这里，我们确定Trithorax基团蛋白Ash21是XI的一个新的成分。Ash21是XIST在向XI维护过渡时与Saf-A和macH2A一起招募的。这些因素的招募是XI染色质组成的发育转折点。令人惊讶的是，表达不会导致基因抑制的突变Xist RNA可以触发Ash21、Saf-A和MacH2A在X染色体上的募集，并可以导致整个染色体上的组蛋白H4低乙酰化。这表明Xist在XI的非基因染色质上建立了一个染色质构型，以提供一个可用于维持基因沉默的抑制室。基因沉默在机械上是可以从这种抑制间隔的形成中分离出来的，因此，需要额外的途径。这一观察结果强调了染色质变化的空间组织在维持X失活中的关键作用。
Mammals compensate X chromosome gene dosage between the sexes by silencing of one of the two female X chromosomes. X inactivation is initiated in the early embryo and requires the non-coding Xist RNA, which encompasses the inactive X chromosome (Xi) and triggers its silencing. In differentiated cells, several factors including the histone variant macroH2A and the scaffold attachment factor SAF-A are recruited to the Xi and maintain its repression. Consequently, in female somatic cells the Xi remains stably silenced independently of Xist. Here, we identify the Trithorax group protein Ash2l as a novel component of the Xi. Ash2l is recruited by Xist concomitantly with Saf-A and macroH2A at the transition to Xi maintenance. Recruitment of these factors characterizes a developmental transition point for the chromatin composition of the Xi. Surprisingly, expression of a mutant Xist RNA that does not cause gene repression can trigger recruitment of Ash2l, Saf-A and macroH2A to the X chromosome, and can cause chromosome-wide histone H4 hypoacetylation. This suggests that a chromatin configuration is established on non-genic chromatin on the Xi by Xist to provide a repressive compartment that could be used for maintaining gene silencing. Gene silencing is mechanistically separable from the formation of this repressive compartment and, thus, requires additional pathways. This observation highlights a crucial role for spatial organization of chromatin changes in the maintenance of X inactivation.