The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice.
The role of maternal-specific H3K9me3 modification in establishing imprinted X-chromosome inactivation and embryogenesis in mice.
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DOI：
10.1038/ncomms6464
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发表时间：
2014-11-14
影响因子：
16.6
通讯作者：
Umezawa, Akihiro
中科院分区：
文献类型：
--
作者：
Fukuda, Atsushi;Tomikawa, Junko;Miura, Takumi;Hata, Kenichiro;Nakabayashi, Kazuhiko;Eggan, Kevin;Akutsu, Hidenori;Umezawa, Akihiro
通过抑制Xist来维持单个活跃的X染色体对小鼠的胚胎发育至关重要。尽管Xist激活子RNF12/RLIM作为母体因子存在，但母体Xist(Xm-Xist)在着床前阶段被抑制，以建立印记X染色体失活(XCI)。在这里，我们证明，使用一种高度可重复性的染色质免疫沉淀方法，促进植入前胚胎的染色质分析，H3K9me3在Xist启动子区域富含，防止RNF12激活XM-Xist。在胚胎干细胞(ES)中，Xist启动子区域高水平的H3K9me3缺失，ES克隆的胚胎表现出RNF12依赖的Xist表达。此外，滋养外胚层缺乏XM-XCI，而不是丢失父系表达的印记基因，是70%-80%的孤雌生殖细胞植入后立即胚胎死亡的主要原因。这项研究表明，H3K9me3参与了使XM-Xist沉默的印记。我们的发现突出了母体特异性的H3K9me3修饰在胚胎发育中的作用。在小鼠着床前阶段，Xist的母体等位基因会受到抑制，Xist编码了X染色体失活所需的一个大的非编码RNA。在这里，作者证明了组蛋白H3在Xist启动子染色质上赖氨酸9的三甲基化是母系决定的Xist抑制的原因。
Maintaining a single active X-chromosome by repressing Xist is crucial for embryonic development in mice. Although the Xist activator RNF12/RLIM is present as a maternal factor, maternal Xist (Xm-Xist) is repressed during preimplantation phases to establish imprinted X-chromosome inactivation (XCI). Here we show, using a highly reproducible chromatin immunoprecipitation method that facilitates chromatin analysis of preimplantation embryos, that H3K9me3 is enriched at the Xist promoter region, preventing Xm-Xist activation by RNF12. The high levels of H3K9me3 at the Xist promoter region are lost in embryonic stem (ES) cells, and ES-cloned embryos show RNF12-dependent Xist expression. Moreover, lack of Xm-XCI in the trophectoderm, rather than loss of paternally expressed imprinted genes, is the primary cause of embryonic lethality in 70–80% of parthenogenotes immediately after implantation. This study reveals that H3K9me3 is involved in the imprinting that silences Xm-Xist. Our findings highlight the role of maternal-specific H3K9me3 modification in embryo development. During mouse preimplantation phases, a repressive imprint is imposed on the maternal allele of Xist, which encodes a large non-coding RNA required for X-chromosome inactivation. Here the authors show that trimethylation of histone H3 at lysine 9 on Xist promoter chromatin is responsible for the maternally determined Xist repression.
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