X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner
X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner
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DOI：
10.1073/pnas.1210787109
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发表时间：
2012-08-07
影响因子：
11.1
通讯作者：
Jaenisch, Rudolf
中科院分区：
文献类型：
--
作者：
Welstead, G. Grant;Creyghton, Menno P.;Jaenisch, Rudolf
胚胎发生需要发育调节因子的及时和协调激活。最近发现的针对抑制性H3K27me3修饰的组蛋白去甲基酶(UTX和JMJD3)在响应特定发育线索的二价基因的激活中发挥了重要作用。为了确定UTX在多能性和发育中的需求，我们产生了UTX缺失的ES细胞和突变小鼠。UTX的缺失在胚胎发育过程中有着深远的影响。UTX基因缺失的胚胎出现在E9.5到E13.5之间的体节数、神经管闭合缺陷和心脏畸形减少。出乎意料的是，纯合子突变的女性胚胎比半合子突变的男性胚胎受到的影响更严重。事实上，我们观察到了UTX缺乏的一部分男性的存活情况，这些男性体型较小，寿命较短。有趣的是，这些动物具有生育能力，精子发生正常。与妊娠中期的致死性一致，UTX缺失的男性和女性ES细胞在畸胎瘤检测中产生了所有三个生殖层，尽管在类胚体检测中可以观察到发育调节因子的激活存在性别差异。最后，CHIP-SEQ分析显示，在UTX缺失的男性ES细胞中，H3K27me3的表达增加。综上所述，我们的数据显示了这种X连锁基因的性别特异性要求，同时暗示了UTY在发育过程中的作用。
Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of "bivalent" genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utx-null ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx-null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males that were smaller in size and had reduced lifespan. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a midgestation lethality, UTX-null male and female ES cells gave rise to all three germ layers in teratoma assays, though sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx-null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development.