Xist RNA repeat E is essential for ASH2L recruitment to the inactive X and regulates histone modifications and escape gene expression.
Xist RNA repeat E is essential for ASH2L recruitment to the inactive X and regulates histone modifications and escape gene expression.
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DOI：
10.1371/journal.pgen.1006890
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Ogawa Y
中科院分区：
文献类型：
--
作者：
Yue M;Ogawa A;Yamada N;Charles Richard JL;Barski A;Ogawa Y
长链非编码RNA Xist在建立和维持X染色体失活（XCI）中起着至关重要的作用，XCI是长链非编码RNA介导的基因调控的范例。Xist具有Xist特异性重复元件A-F，其在真兽目哺乳动物中是保守的，强调了其功能的重要性。在这里，我们报告，Xist RNA重复序列E，Xist外显子7中的一个保守的Xist重复序列元件，与ASH 2L相互作用，并有助于维持逃逸基因表达水平的非活性X染色体（Xi）在XCI。Xist重复E缺失突变体雌性ES细胞显示在分化时来自Xi的ASH 2L的消耗。此外，逃逸基因的子集在重复E突变体细胞中表现出出乎意料地比在X失活期间表达野生型Xist的细胞更高的表达，而X连锁的非逃逸基因的沉默不受影响。我们讨论了这些结果的影响，以了解在随机X染色体失活过程中的组蛋白修饰和逃逸基因调控的ASH 2L和Xist重复序列E的作用。Xist长非编码RNA通过募集多个染色质修饰酶到失活的X染色体来诱导X染色体失活。在这些染色质修饰酶中，ASH 2L是独特的，因为它是MLL/SET复合物的组分，MLL/SET复合物是用于转录激活的组蛋白赖氨酸4甲基转移酶。在我们论文的新结果中，我们发现ASH 2L与Xist RNA的重复序列E结合。使用Xist重复序列E缺失突变体细胞，我们发现Xist RNA的重复序列E对于X连锁基因沉默是不必要的，但对于维持逃逸基因表达的适当水平是必需的。这是第一个报告表明，Xist RNA不仅参与X连锁基因沉默，而且参与逃逸基因调控。
Long non-coding RNA Xist plays a crucial role in establishing and maintaining X-chromosome inactivation (XCI) which is a paradigm of long non-coding RNA-mediated gene regulation. Xist has Xist-specific repeat elements A-F which are conserved among eutherian mammals, underscoring their functional importance. Here we report that Xist RNA repeat E, a conserved Xist repeat element in the Xist exon 7, interacts with ASH2L and contributes to maintenance of escape gene expression level on the inactive X-chromosome (Xi) during XCI. The Xist repeat E-deletion mutant female ES cells show the depletion of ASH2L from the Xi upon differentiation. Furthermore, a subset of escape genes exhibits unexpectedly higher expression in the repeat E mutant cells than the cells expressing wildtype Xist during X-inactivation, whereas the silencing of X-linked non-escape genes is not affected. We discuss the implications of these results to understand the role of ASH2L and Xist repeat E for histone modifications and escape gene regulation during random X-chromosome inactivation. Xist long noncoding RNA induces X chromosome inactivation by recruiting multiple chromatin modifying enzymes to the inactive X-chromosome. Among such chromatin modifying enzymes, ASH2L is unique since it is a component of the MLL/SET complexes, which are a histone lysine 4 methyltransferase for transcriptional activation. Among the novel results in our paper, we found that ASH2L binds to the repeat E of Xist RNA. Using the Xist repeat E deletion mutant cells, we discovered that the repeat E of Xist RNA is dispensable for X-linked gene silencing, but is required for maintaining proper level of escape gene expression. This is the first report indicating that Xist RNA engages not only in X-linked gene silencing but also in escape gene regulation.
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影响因子：
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