Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice
Differential methylation of Xite and CTCF sites in Tsix mirrors the pattern of X-inactivation choice in mice
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DOI：
10.1128/mcb.26.6.2109-2117.2006
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Lee, JT
中科院分区：
文献类型：
--
作者：
Boumil, RM;Ogawa, Y;Lee, JT
在哺乳动物剂量补偿期间，雌性细胞中两条X染色体中的一条失活。选择哪个X被沉默可以是印记的或随机的。虽然影响选择决定的遗传位点已经确定，印记和随机选择的主要标志仍然不确定。在这里，我们研究了DNA甲基化的作用，这是一种已知的调节常染色体基因座印迹的机制，并试图确定两个X上的差异甲基化是否可以预测它们的命运。为了确定差异甲基化结构域（DMD）在X-失活中心，我们使用亚硫酸氢盐测序和甲基化敏感的限制性内切酶分析。我们在Tsix和Xite中发现了DMD，这两个基因以前被证明会影响选择。有趣的是，Tsix中的DMD位于CTCF结合位点内。等位基因甲基化差异发生在配子中，并在携带两个活性X的胚胎干细胞中被消除。由于DNA甲基化的模式反映了X-失活的事件，我们提出Tsix和Xite中DMD的差异甲基化构成了表观遗传调控的主要标志。CTCF位点DMD的发现进一步揭示了X失活和常染色体印记之间的相似性。
During mammalian dosage compensation, one of two X-chromosomes in female cells is inactivated. The choice of which X is silenced can be imprinted or stochastic. Although genetic loci influencing the choice decision have been identified, the primary marks for imprinting and random selection remain undefined. Here, we examined the role of DNA methylation, a mechanism known to regulate imprinting in autosomal loci, and sought to determine whether differential methylation on the two Xs might predict their fates. To identify differentially methylated domains (DMDs) at the X-inactivation center, we used bisulfite sequencing and methylation-sensitive restriction enzyme analyses. We found DMDs in Tsix and Xite, two genes previously shown to influence choice. Interestingly, the DMDs in Tsix lie within CTCF binding sites. Allelic methylation differences occur in gametes and are erased in embryonic stem cells carrying two active Xs. Because the pattern of DNA methylation mirrors events of X-inactivation, we propose that differential methylation of DMDs in Tsix and Xite constitute a primary mark for epigenetic regulation. The discovery of DMDs in CTCF sites draws further parallels between X-inactivation and autosomal imprinting.