RNF12 Activates Xist and Is Essential for X Chromosome Inactivation
RNF12 Activates Xist and Is Essential for X Chromosome Inactivation
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DOI：
10.1371/journal.pgen.1002001
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发表时间：
2011-01-01
期刊：
影响因子：
4.5
通讯作者：
Gribnau, Joost
中科院分区：
文献类型：
--
作者：
Barakat, Tahsin Stefan;Gunhanlar, Nilhan;Gribnau, Joost
在雌性胎盘哺乳动物的体细胞中，两条X染色体中的一条被转录沉默，以在雄性和雌性中实现相等剂量的X编码基因产物。随机X染色体失活（XCI）的启动被认为是由X编码的激活子和控制Xist的常染色体编码的抑制子调控的。Xist RNA的扩散导致X染色体顺式沉默。在这里，我们证明了剂量依赖性X编码的XCI激活剂RNF12/RLIM反式作用并激活Xist。我们没有发现RNF12通过Tsix或Xist内含子1区域介导的XCI调节的证据，这两个区域都已知参与Xist的抑制。此外，我们发现，Xist内含子1，其中包含一个多能性因子结合位点，是不需要抑制Xist在未分化的ES细胞。对雌性Rnf12（-/-）敲除ES细胞的分析表明，RNF12对于XCI的启动是必需的，并且主要参与Xist的调节。我们的结论是RNF12是上调Xist转录的一个不可或缺的因素，从而导致随机XCI的启动。
In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12(-/-) knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.