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A prominent and conserved role for YY1 in Xist transcriptional activation

机译：YY1在Xist转录激活中的突出和保守作用

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Dosage compensation for X-linked genes in female mammalsrelies on X-chromosome inactivation. This processinvolves monoallelic up-regulation of the non-coding XistRNA which coats in cis the chromosome and triggers epigeneticreprogramming that will prevent chromosomewidetranscription. Xist transcription is controlled, directlyand/or indirectly, by several ncRNA (Tsix, Jpx, Ftx) andfactors (Sox2, Oct4, Nanog, Rex1, Rnf12). However,mechanisms leading to Xist monoallelic regulation remainpoorly understood.Using mouse ES and differentiating cells, we identifiedspecific YY1 and CTCF interacting sites on the Xist locusof the inactive X-chromosome. We show that this monoallelicbinding is controlled by DNA methylation. To gainfurther insights into YY1 functional role on the Xist locus,we conducted YY1 knockdown experiments. We show byRNA-FISH that depletion of YY1 in female somatic cellsimpairs the accumulation of Xist on the inactive X-chromosome.This is likely due to a transcriptional effect as weobserve a drastic reduction of both spliced and unsplicedXist RNA levels. This hypothesis is further reinforced bythe in vitro analysis Xist promoter activity, which displaysstrict dependency on the YY1 binding sites. Importantly,YY1 is also necessary for the upregulation of Xist that triggersX-chromosome inactivation. Taken together, theseresults suggest a strong requirement for YY1 in the upregulationand maintenance of Xist transcription. Importantly,we demonstrate that the function of YY1 in thecontrol of Xist expression is conserved in humans and predictedin other mammalian species.These results highlight the importance of YY1 both inthe monoallelic upregulation of Xist at the exit of pluripotencyand in the maintenance of its expression in somaticcells. Taken together with previous studies, we proposethat through its dual action on Tsix and Xist, YY1 acts asa bimodal transcriptional regulator of X-inactivation.
机译：雌性哺乳动物中X连锁基因的剂量补偿依赖于X染色体失活。此过程涉及非编码XistRNA的单等位基因上调，该XistRNA覆盖顺式染色体并触发表观遗传重编程，这将阻止染色体全转录。 Xist转录受几种ncRNA（Tsix，Jpx，Ftx）和因子（Sox2，Oct4，Nanog，Rex1，Rnf12）直接和/或间接控制。然而，导致Xist单等位基因调控的机制仍知之甚少。使用小鼠ES和分化细胞，我们在非活性X染色体的Xist位点上鉴定了特定的YY1和CTCF相互作用位点。我们表明，这种单等位基因结合是由DNA甲基化控制的。为了进一步了解YY1在Xist基因座上的功能，我们进行了YY1敲低实验。我们通过RNA-FISH显示，女性体细胞中YY1的耗尽会削弱Xist在非活性X染色体上的积累，这很可能是由于转录效应，因为我们观察到剪接和未剪接的Xist RNA水平都急剧降低。体外分析Xist启动子活性进一步证实了这一假设，该活性显示出对YY1结合位点的严格依赖性。重要的是，YY1对于触发X染色体失活的Xist的上调也是必需的。综上所述，这些结果表明在上调和维持Xist转录中强烈需要YY1。重要的是，我们证明了YY1在Xist表达控制中的功能在人类中是保守的，并且在其他哺乳动物物种中也得到了预测。这些结果突显了YY1在Xist的单等位基因多能性上调和维持其在体细胞表达中的重要性。 。结合以前的研究，我们建议YY1通过对Tsix和Xist的双重作用，充当X灭活的双峰转录调节因子。

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