3月,，國(guó)際學(xué)術(shù)期刊The Journal of Biological Chemistry發(fā)表了上海生科院/上海交大醫(yī)學(xué)院健康所,，中國(guó)科學(xué)院干細(xì)胞生物學(xué)重點(diǎn)實(shí)驗(yàn)室干細(xì)胞研究組的最新研究進(jìn)展,。
胚胎干細(xì)胞（embryonic stem, ES）來(lái)源于著床前胚胎囊胚時(shí)期的內(nèi)細(xì)胞團(tuán),，在體外可以無(wú)限擴(kuò)增,，并具有分化為各種成熟的體細(xì)胞的能力,，這些特性使胚胎干細(xì)胞無(wú)論在基礎(chǔ)研究還是在臨床應(yīng)用上，都具有非常重要的價(jià)值,。近年來(lái)，由體細(xì)胞重編程所得的誘導(dǎo)性多能干（induced pluripotent stem,，iPS）細(xì)胞的建立進(jìn)一步拉近了ES細(xì)胞和臨床疾病治療的距離,。同時(shí)，深入了解ES細(xì)胞的自我更新調(diào)控和分化潛能維持的分子機(jī)制,，也成為科學(xué)家們共同關(guān)注的焦點(diǎn)之一,。
近年來(lái)的研究發(fā)現(xiàn)：Tbx3是一個(gè)維持ES細(xì)胞自我更新的重要轉(zhuǎn)錄因子，同時(shí)Tbx3也可以提高iPS細(xì)胞的質(zhì)量,。在金穎研究員的指導(dǎo)下，干細(xì)胞研究組博士研究生盧銳等對(duì)Tbx3的功能進(jìn)行了進(jìn)一步的探索,。研究發(fā)現(xiàn)，下調(diào)小鼠ES細(xì)胞中Tbx3的表達(dá)水平,，不僅使ES細(xì)胞的自我更新能力下降，同時(shí)也導(dǎo)致原始內(nèi)胚層標(biāo)志基因的表達(dá)水平下降,。通過(guò)類胚體分化以及體外定向分化的方法，發(fā)現(xiàn)下調(diào)Tbx3的表達(dá)阻礙了原始內(nèi)胚層的分化過(guò)程,。與之相對(duì)應(yīng)的是,，在ES細(xì)胞中過(guò)表達(dá)Tbx3則引起原始內(nèi)胚層樣的分化。進(jìn)一步的研究和分析表明：Tbx3直接結(jié)合在原始內(nèi)胚層分化的關(guān)鍵調(diào)控蛋白Gata6基因的啟動(dòng)子上,，并激活該基因的表達(dá),，這一過(guò)程也伴隨著Gata6啟動(dòng)子上轉(zhuǎn)錄抑制復(fù)合物2（PRC2）的減少和H3K27me3修飾水平的降低。
該項(xiàng)研究首次發(fā)現(xiàn)了Tbx3在調(diào)控ES細(xì)胞命運(yùn)上具有雙重功能,，即不僅維持了ES細(xì)胞的自我更新,，而且維持了ES細(xì)胞向原始內(nèi)胚層方向分化的能力。這一研究成果為全面認(rèn)識(shí)胚胎干細(xì)胞全能性轉(zhuǎn)錄因子的功能提供了新的視角,。
該項(xiàng)工作得到了國(guó)家自然科學(xué)基金,、國(guó)家高技術(shù)研究發(fā)展計(jì)劃、上海市科技啟明星計(jì)劃和上海市重點(diǎn)學(xué)科建設(shè)項(xiàng)目的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
The Journal of Biological Chemistry March 11, 2011 doi: 10.1074/jbc.M110.202150
Dual Functions of T-Box 3 (Tbx3) in the Control of Self-renewal and Extraembryonic Endoderm Differentiation in Mouse Embryonic Stem Cells*
Rui Lu, Acong Yang and Ying Jin
Embryonic stem cells (ESCs) possess the capacity to proliferate indefinitely in an undifferentiated state and to differentiate into various cell types in an organism. However, the critical question of how self-renewal and differentiation are precisely regulated in ESCs is not entirely understood at present. Here, we report the essential role of Tbx3, a pluripotency-related transcription factor of the T-box gene family, for both the maintenance of self-renewal of mouse ESCs and for their differentiation into extraembryonic endoderm (ExEn). We show that Tbx3 is highly expressed in ExEn cells in addition to undifferentiated ESCs. Knockdown of Tbx3 expression using tetracycline-regulated Tbx3 siRNA resulted in the attenuation of ESC self-renewal ability and aberrant differentiation processes, including reduced ExEn differentiation but enhanced ectoderm and trophectoderm differentiation. Conversely, inducible forced expression of Tbx3 triggered ExEn lineage commitment. Mechanistically, Tbx3 directly activated the expression of Gata6, an essential regulator of ExEn. Interestingly, Tbx3 modulated H3K27me3 modification and the association of the PRC2 complex with the promoter region of Gata6. Taken together, the results of this study revealed a previously unappreciated role of a pluripotency factor in ExEn differentiation. Additionally, our data reveal that Tbx3 may function through direct binding and epigenetic modification of histones on the Gata6 promoter to maintain the ExEn differentiation potential of ESCs.
