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Histone H3 Lysine 36 Trimethylation Is Established over the Xist Promoter by Antisense Tsix Transcription and Contributes to Repressing Xist Expression

机译:组蛋白H3赖氨酸36三甲基化通过反义Tsix转录建立在Xist启动子上,并有助于抑制Xist表达

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One of the two X chromosomes in female mammals is inactivated by the noncoding Xist RNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNA Tsix, which represses Xist on the active X chromosome. In the absence of Tsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over the Xist promoter. Simultaneous disruption of Tsix and PRC2 leads to derepression of Xist and in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited by Tsix cotranscriptionally and extends over the Xist promoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression of Xist. Moreover, depletion of the H3K36 methylase Setd2 leads to upregulation of Xist, suggesting H3K36me3 as a modification that contributes to the mechanism of Tsix function in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over the Xist promoter, indicating that additional mechanisms exist by which Tsix blocks PRC2 recruitment to the Xist promoter.
机译:雌性哺乳动物的两个X染色体之一被非编码的 Xist RNA灭活。在小鼠中,X染色体失活(XCI)受反义RNA Tsix 调控,该RNA抑制活跃X染色体上的 Xist 。在没有 Tsix 的情况下,在 Xist 启动子上建立了PRC2介导的组蛋白H3赖氨酸27三甲基化(H3K27me3)。同时破坏 Tsix 和PRC2导致 Xist 的抑制,进而使雄性胚胎干细胞中的单个X染色体沉默。在这里,我们确定了组蛋白H3赖氨酸36三甲基化(H3K36me3)是由 Tsix 共转录募集并延伸到 Xist 启动子的修饰。通过突变的组蛋白H3.3的表达,在36位上用蛋氨酸替代赖氨酸来还原H3K36me3,会导致 Xist 的显着抑制。此外,H3K36甲基化酶 Setd2 的耗尽会导致 Xist 的上调,这表明H3K36me3是一种修饰,有助于 Tsix 调节功能XCI。此外,我们发现H3K36me3的减少并不能促进H3K27me3相对于 Xist 启动子的增加,表明存在其他机制, Tsix 阻止PRC2募集到 Xist 启动子。

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