G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We show that G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence Xist in cis. Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.

中文翻译：

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G9a甲基转移酶缺乏对X染色体的不成比例的影响

G9a 是一种组蛋白甲基转移酶，负责组蛋白 H3 在赖氨酸 9 (H3K9me2) 的二甲基化。G9a 在发育调节基因的转录沉默中起关键作用，但其在 X 染色体失活 (XCI) 中的作用一直存在争议。在这里，我们发现了 G9a 的女性特异性功能，并证明删除 G9a 对 X 染色体的影响相对于基因组的其余部分不成比例。G9a 缺乏导致 XCI 失败和女性对 H3K9me2 药物抑制的特异性超敏反应。我们显示 G9a 与 Tsix 和 Xist RNA 相互作用，并且 G9a-RNA 相互作用的竞争性抑制概括了 XCI 缺陷。在 XCI 期间，Xist 招募 G9a 以沉默未来非活动 X 上的 X 连锁基因。在未来 Xa 上平行地，Tsix 招募 G9a 以沉默Xist在顺式。因此，用于 H3K9me2 修饰的等位基因特异性靶向的 RNA 束缚 G9a 和 G9a-RNA 相互作用对于 XCI 是必不可少的。