3月，國際學術期刊The Journal of Biological Chemistry發(fā)表了上海生科院/上海交大醫(yī)學院健康所,，中國科學院干細胞生物學重點實驗室干細胞研究組的最新研究進展,。
胚胎干細胞（embryonic stem, ES）來源于著床前胚胎囊胚時期的內(nèi)細胞團，在體外可以無限擴增，并具有分化為各種成熟的體細胞的能力,，這些特性使胚胎干細胞無論在基礎研究還是在臨床應用上,，都具有非常重要的價值。近年來,，由體細胞重編程所得的誘導性多能干（induced pluripotent stem,，iPS）細胞的建立進一步拉近了ES細胞和臨床疾病治療的距離。同時,，深入了解ES細胞的自我更新調(diào)控和分化潛能維持的分子機制,，也成為科學家們共同關注的焦點之一。
近年來的研究發(fā)現(xiàn)：Tbx3是一個維持ES細胞自我更新的重要轉(zhuǎn)錄因子,，同時Tbx3也可以提高iPS細胞的質(zhì)量,。在金穎研究員的指導下，干細胞研究組博士研究生盧銳等對Tbx3的功能進行了進一步的探索,。研究發(fā)現(xiàn),，下調(diào)小鼠ES細胞中Tbx3的表達水平，不僅使ES細胞的自我更新能力下降,，同時也導致原始內(nèi)胚層標志基因的表達水平下降,。通過類胚體分化以及體外定向分化的方法，發(fā)現(xiàn)下調(diào)Tbx3的表達阻礙了原始內(nèi)胚層的分化過程,。與之相對應的是,，在ES細胞中過表達Tbx3則引起原始內(nèi)胚層樣的分化。進一步的研究和分析表明：Tbx3直接結(jié)合在原始內(nèi)胚層分化的關鍵調(diào)控蛋白Gata6基因的啟動子上,，并激活該基因的表達,，這一過程也伴隨著Gata6啟動子上轉(zhuǎn)錄抑制復合物2（PRC2）的減少和H3K27me3修飾水平的降低。
該項研究首次發(fā)現(xiàn)了Tbx3在調(diào)控ES細胞命運上具有雙重功能,，即不僅維持了ES細胞的自我更新,，而且維持了ES細胞向原始內(nèi)胚層方向分化的能力。這一研究成果為全面認識胚胎干細胞全能性轉(zhuǎn)錄因子的功能提供了新的視角,。
該項工作得到了國家自然科學基金,、國家高技術研究發(fā)展計劃、上海市科技啟明星計劃和上海市重點學科建設項目的資助,。（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.
