在雌雄哺乳動(dòng)物個(gè)體中,，X染色體的數(shù)目不同，為保證雌性個(gè)體不會(huì)有多余的X染色體基因產(chǎn)物,，需要一種途徑來解決雌雄個(gè)體X染色體計(jì)量上的差異,，在雌性哺乳動(dòng)物中，通過劑量補(bǔ)償(dosage compensation）來隨機(jī)失活2條X染色體中的一條,。
Xist基因與X染色體失活有著密切關(guān)系,，在雌性個(gè)體中，失活的X染色體周圍包裹著大量Xist基因的轉(zhuǎn)錄物,。與之相反,，活化的X染色體周圍包裹著Tsix基因的轉(zhuǎn)錄物。而Tsix正是Xist的反義序列,。
本文作者在過去的研究中發(fā)現(xiàn),，由X染色體編碼的E3泛素連接酶RNF12在小鼠胚胎干細(xì)胞的分化過程中表達(dá)量上調(diào)。該蛋白可以提高Xist的轉(zhuǎn)錄活性,，從而促進(jìn)X染色體沉默,，但這一過程中具體的機(jī)制尚不清楚。
本文中,，研究者認(rèn)為,，多能性因子REX1是RNF12在失活X染色體過程中的重要靶蛋白，RNF12能通過泛素化途徑降解REX1,。在敲除了RNF12的胚胎干細(xì)胞中,，REX1的表達(dá)水平上調(diào)。研究者通過染色質(zhì)免疫共沉淀技術(shù)在X染色體上Xist與Tsix的結(jié)合區(qū)域找到REX1的結(jié)合位點(diǎn),。在雌性胚胎干細(xì)胞中,，過表達(dá)REX1會(huì)抑制Xist的轉(zhuǎn)錄和X染色體的失活。而REX1雜合的雄性胚胎干細(xì)胞表現(xiàn)出異位X染色體失活,。研究人員就此得出,，RNF12通過下調(diào)REX1導(dǎo)致X染色體沉默，這是X染色體失活機(jī)制中的一條重要途徑,。此外，REX1與Xist只在哺乳動(dòng)物中表達(dá),，說明這兩個(gè)基因是與X染色體沉默共同進(jìn)化的,。（生物谷 Bioon.com ）
doi:10.1038/nature11070
PMC:
PMID:
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.
