RNF12 Is an X-Encoded Dose-Dependent Activator of X Chromosome Inactivation
RNF12 Is an X-Encoded Dose-Dependent Activator of X Chromosome Inactivation
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DOI：
10.1016/j.cell.2009.10.034
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发表时间：
2009-11-25
期刊：
影响因子：
64.5
通讯作者：
Gribnau, Joost
中科院分区：
文献类型：
--
作者：
Jonkers, Iris;Barakat, Tahsin Stefan;Gribnau, Joost
在雌性胎盘哺乳动物的体细胞中，一条X染色体失活，以尽量减少与性别相关的X编码基因的剂量差异。胚胎中的随机X染色体失活（Random X chromosome inactivation， XCI）是一个随机过程，其中每个X有独立的概率启动XCI，由一个或多个X编码的XCI激活子的核浓度触发。在这里，我们发现E3泛素连接酶RNF12是一个重要的xci激活剂。小鼠Rnf12或人类Rnf12的额外拷贝导致雄性小鼠胚胎干细胞和相当比例的雌性小鼠胚胎干细胞中两条X染色体上的XCI起始。这种活性依赖于Rnf12完整的开放阅读框，并与Rnf12的转基因表达水平相关。在分化雌性杂合子Rnf12（+/-）胚胎干细胞中，XCI的起始明显减少。这些发现为RNF12在XCI计数和启动过程中的剂量依赖性作用提供了证据。
In somatic cells of female placental mammals, one X chromosome is inactivated to minimize sex-related dosage differences of X-encoded genes. Random X chromosome inactivation (XCI) in the embryo is a stochastic process, in which each X has an independent probability to initiate XCI, triggered by the nuclear concentration of one or more X-encoded XCI-activators. Here, we identify the E3 ubiquitin ligase RNF12 as an important XCI-activator. Additional copies of mouse Rnf12 or human RNF12 result in initiation of XCI in male mouse ES cells and on both X chromosomes in a substantial percentage of female mouse ES cells. This activity is dependent on an intact open reading frame of Rnf12 and correlates with the transgenic expression level of RNF12. Initiation of XCI is markedly reduced in differentiating female heterozygous Rnf12(+/-) ES cells. These findings provide evidence for a dose-dependent role of RNF12 in the XCI counting and initiation process.