Jonkers Iris, Barakat Tahsin Stefan, Achame Eskeatnaf Mulugeta, Monkhorst Kim, Kenter Annegien, Rentmeester Eveline, Grosveld Frank, Grootegoed J Anton, Gribnau Joost
Department of Reproduction and Development, Erasmus MC, University Medical Center, 3000 CA Rotterdam, The Netherlands.
Cell. 2009 Nov 25;139(5):999-1011. doi: 10.1016/j.cell.2009.10.034.
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.
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X编码基因与性别相关的剂量差异。胚胎中的随机X染色体失活（XCI）是一个随机过程，其中每条X染色体都有独立的启动XCI的概率，由一种或多种X编码的XCI激活因子的核浓度触发。在这里，我们确定E3泛素连接酶RNF12是一种重要的XCI激活因子。额外拷贝的小鼠Rnf12或人类RNF12会导致雄性小鼠胚胎干细胞中XCI的启动，以及相当比例的雌性小鼠胚胎干细胞中两条X染色体上XCI的启动。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。在分化的雌性杂合Rnf12(+/-)胚胎干细胞中，XCI的启动明显减少。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。
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