A chromosomal memory triggered by Xist regulates histone methylation in X inactivation.
A chromosomal memory triggered by Xist regulates histone methylation in X inactivation.
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DOI：
10.1371/journal.pbio.0020171
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发表时间：
2004-07
期刊：
影响因子：
9.8
通讯作者：
Wutz A
中科院分区：
文献类型：
--
作者：
Kohlmaier A;Savarese F;Lachner M;Martens J;Jenuwein T;Wutz A
我们利用诱导的Xist表达系统阐明了小鼠胚胎干细胞中X失活过程中组蛋白甲基化的动力学。先前的报道表明，Xist触发沉默的能力仅限于胚胎干细胞分化的早期窗口。在这里，我们发现这个窗口对于在潜在的失活X染色体上建立甲基化模式也很重要。通过免疫荧光和染色质免疫沉淀实验，我们发现组蛋白H3赖氨酸27三甲基化（H3K27m3）和H4赖氨酸20单甲基化（H4K20m1）与未分化ES细胞中的Xist表达相关，并标志着X失活的开始。这两种标记都依赖于Xist RNA的定位，但与沉默无关。在起始窗口后诱导Xist表达导致诱导H3K27m3的能力显著降低，而在限制性时间点之前表达则可以有效地建立H3K27m3。我们的数据表明，在胚胎干细胞分化的早期，Xist的表达建立了染色体记忆，这种记忆在没有沉默的情况下得以维持。这种记忆的一个结果是能够在早期表达Xist的染色体上的限制性时间点之后有效地引入H3K27m3。我们的研究结果表明，这种不依赖于沉默的染色体记忆对X失活的维持具有重要意义，在X失活中，以前自我延续的异染色质结构被视为记忆的主要形式。雌性哺乳动物有一条X染色体失活。Anton Wutz和他的同事们发现了一个非常早期的事件的证据，该事件“标记”了染色体未来稳定失活的迹象
We have elucidated the kinetics of histone methylation during X inactivation using an inducible Xist expression system in mouse embryonic stem (ES) cells. Previous reports showed that the ability of Xist to trigger silencing is restricted to an early window in ES cell differentiation. Here we show that this window is also important for establishing methylation patterns on the potential inactive X chromosome. By immunofluorescence and chromatin immunoprecipitation experiments we show that histone H3 lysine 27 trimethylation (H3K27m3) and H4 lysine 20 monomethylation (H4K20m1) are associated with Xist expression in undifferentiated ES cells and mark the initiation of X inactivation. Both marks depend on Xist RNA localisation but are independent of silencing. Induction of Xist expression after the initiation window leads to a markedly reduced ability to induce H3K27m3, whereas expression before the restrictive time point allows efficient H3K27m3 establishment. Our data show that Xist expression early in ES cell differentiation establishes a chromosomal memory, which is maintained in the absence of silencing. One consequence of this memory is the ability to introduce H3K27m3 efficiently after the restrictive time point on the chromosome that has expressed Xist early. Our results suggest that this silencing-independent chromosomal memory has important implications for the maintenance of X inactivation, where previously self-perpetuating heterochromatin structures were viewed as the principal form of memory. In female mammals, one X chromosome is inactivated. Anton Wutz and colleagues find evidence for a very early event that 'marks' the chromosome for future stable inactivation
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