在雌雄哺乳动物个体中，X染色体的数目不同，为保证雌性个体不会有多余的X染色体基因产物，需要一种途径来解决雌雄个体X染色体计量上的差异，在雌性哺乳动物中，通过剂量补偿(dosage compensation）来随机失活2条X染色体中的一条。
Xist基因与X染色体失活有着密切关系，在雌性个体中，失活的X染色体周围包裹着大量Xist基因的转录物。与之相反，活化的X染色体周围包裹着Tsix基因的转录物。而Tsix正是Xist的反义序列。
本文作者在过去的研究中发现，由X染色体编码的E3泛素连接酶RNF12在小鼠胚胎干细胞的分化过程中表达量上调。该蛋白可以提高Xist的转录活性，从而促进X染色体沉默，但这一过程中具体的机制尚不清楚。
本文中，研究者认为，多能性因子REX1是RNF12在失活X染色体过程中的重要靶蛋白，RNF12能通过泛素化途径降解REX1。在敲除了RNF12的胚胎干细胞中，REX1的表达水平上调。研究者通过染色质免疫共沉淀技术在X染色体上Xist与Tsix的结合区域找到REX1的结合位点。在雌性胚胎干细胞中，过表达REX1会抑制Xist的转录和X染色体的失活。而REX1杂合的雄性胚胎干细胞表现出异位X染色体失活。研究人员就此得出，RNF12通过下调REX1导致X染色体沉默，这是X染色体失活机制中的一条重要途径。此外，REX1与Xist只在哺乳动物中表达，说明这两个基因是与X染色体沉默共同进化的。（生物谷 Bioon.com ）
doi:10.1038/nature11070
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RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation
Cristina Gontan, Eskeatnaf Mulugeta Achame, Jeroen Demmers, Tahsin Stefan Barakat, Eveline Rentmeester, Wilfred van IJcken, J. Anton Grootegoed & Joost Gribnau .
Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells1. Upregulation of Xist transcription on the future inactive X chromosome acts against Tsix antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates Xist transcription and X-chromosome inactivation2. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in Xist and Tsix regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit Xist transcription and X-chromosome inactivation, whereas male Rex1+/− embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation. Rex1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.
