取出一個(gè)成熟細(xì)胞并移除其身份,,從而使其可成為任何種類細(xì)胞——核重組,,在修復(fù)受損組織及在化療后替換骨髓等領(lǐng)域具有廣闊前景,。2012年諾貝爾醫(yī)學(xué)獎(jiǎng)得主約翰·格登博士最新發(fā)表在《表觀遺傳學(xué)和染色質(zhì)研究》(Epigenetics & Chromatin)雜志上的論文表明,由Hira蛋白存儲(chǔ)的組蛋白H3.3,,是將細(xì)胞核恢復(fù)多能性,,即發(fā)展成為多種細(xì)胞類型的關(guān)鍵一步。
所有個(gè)體的細(xì)胞都有相同的DNA(脫氧核糖核酸),隨著生物體的成熟,,這些細(xì)胞可被重組為心臟,、肺、大腦等不同類型,。為實(shí)現(xiàn)這一目標(biāo),,不同的基因或多或少會(huì)在每個(gè)細(xì)胞譜系中永久關(guān)閉。隨著胚胎的生長,,經(jīng)一定數(shù)量的分化后,,沿著某條道路走下去的細(xì)胞將不再變成其他的東西。例如,,心臟細(xì)胞不能轉(zhuǎn)化為肺組織,,肌肉細(xì)胞也不能形成骨頭。
重組DNA的一個(gè)方法是,,將一個(gè)成熟細(xì)胞的細(xì)胞核轉(zhuǎn)移到一個(gè)未受精的卵子中,。卵子中的蛋白質(zhì)及其他因子,將使DNA打開某些基因的同時(shí)關(guān)閉其他基因,,直到它類似于一個(gè)多能細(xì)胞的DNA,。但是,以這種方法完全抹去細(xì)胞的“記憶”似乎不太容易,。
調(diào)節(jié)基因活性的機(jī)制之一是染色質(zhì),,特別是組蛋白。DNA纏繞在組蛋白上,,其纏繞方式的變化將改變細(xì)胞可用的基因,。為了了解核重組的工作原理,格登博士領(lǐng)導(dǎo)的研究團(tuán)隊(duì)將小鼠的細(xì)胞核移植到青蛙的卵母細(xì)胞中,,并透過顯微注射方式添加了熒光標(biāo)記組蛋白,,以觀察組蛋白在細(xì)胞和細(xì)胞核內(nèi)的什么地方聚集。
研究小組使用實(shí)時(shí)顯微鏡明顯觀察到,,從第10小時(shí)起,,在卵母細(xì)胞中表達(dá)的H3.3組蛋白(參與基因的激活)開始并入移植的細(xì)胞核內(nèi)。當(dāng)研究人員查看Oct4基因(參與形成細(xì)胞多能性)處的細(xì)節(jié)情況時(shí),,他們發(fā)現(xiàn)H3.3組蛋白也被納入Oct4,,與此同時(shí)基因開始轉(zhuǎn)錄。研究小組還發(fā)現(xiàn),,Hira組蛋白(需要H3.3協(xié)同進(jìn)入染色質(zhì))也需要核重組,。
遺傳專家指出,操縱H3.3的路徑,,或許可為完全抹除細(xì)胞“記憶”并產(chǎn)生一個(gè)真正的多能細(xì)胞提供一種新方法。研究表明,染色質(zhì)是防止臨床上常用的人為誘導(dǎo)重組的關(guān)鍵所在,。(生物谷Bioon.com)
doi:10.1186/1756-8935-5-17
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HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes
Jerome Jullien1*, Carolina Astrand1, Emmanuelle Szenker2, Nigel Garrett1, Genevieve Almouzni2 and John B Gurdon1
Background Nuclear reprogramming is potentially important as a route to cell replacement and drug discovery, but little is known about its mechanism. Nuclear transfer to eggs and oocytes attempts to identify the mechanism of this direct route towards reprogramming by natural components. Here we analyze how the reprogramming of nuclei transplanted to Xenopus oocytes exploits the incorporation of the histone variant H3.3. Results After nuclear transplantation, oocyte-derived H3.3 but not H3.2, is deposited on several regions of the genome including rDNA, major satellite repeats, and the regulatory regions of Oct4. This major H3.3 deposition occurs in absence of DNA replication, and is HIRA-and transcription-dependent. It is necessary for the shift from a somatic- to an oocyte-type of transcription after nuclear transfer. Conclusions This study demonstrates that the incorporation of histone H3.3 is an early and necessary step in the direct reprogramming of somatic cell nuclei by oocyte. It suggests that the incorporation of histone H3.3 is necessary during global changes in transcription that accompany changes in cell fate.