3月，国际学术期刊The Journal of Biological Chemistry发表了上海生科院/上海交大医学院健康所，中国科学院干细胞生物学重点实验室干细胞研究组的最新研究进展。
胚胎干细胞（embryonic stem, ES）来源于着床前胚胎囊胚时期的内细胞团，在体外可以无限扩增，并具有分化为各种成熟的体细胞的能力，这些特性使胚胎干细胞无论在基础研究还是在临床应用上，都具有非常重要的价值。近年来，由体细胞重编程所得的诱导性多能干（induced pluripotent stem，iPS）细胞的建立进一步拉近了ES细胞和临床疾病治疗的距离。同时，深入了解ES细胞的自我更新调控和分化潜能维持的分子机制，也成为科学家们共同关注的焦点之一。
近年来的研究发现：Tbx3是一个维持ES细胞自我更新的重要转录因子，同时Tbx3也可以提高iPS细胞的质量。在金颖研究员的指导下，干细胞研究组博士研究生卢锐等对Tbx3的功能进行了进一步的探索。研究发现，下调小鼠ES细胞中Tbx3的表达水平，不仅使ES细胞的自我更新能力下降，同时也导致原始内胚层标志基因的表达水平下降。通过类胚体分化以及体外定向分化的方法，发现下调Tbx3的表达阻碍了原始内胚层的分化过程。与之相对应的是，在ES细胞中过表达Tbx3则引起原始内胚层样的分化。进一步的研究和分析表明：Tbx3直接结合在原始内胚层分化的关键调控蛋白Gata6基因的启动子上，并激活该基因的表达，这一过程也伴随着Gata6启动子上转录抑制复合物2（PRC2）的减少和H3K27me3修饰水平的降低。
该项研究首次发现了Tbx3在调控ES细胞命运上具有双重功能，即不仅维持了ES细胞的自我更新，而且维持了ES细胞向原始内胚层方向分化的能力。这一研究成果为全面认识胚胎干细胞全能性转录因子的功能提供了新的视角。
该项工作得到了国家自然科学基金、国家高技术研究发展计划、上海市科技启明星计划和上海市重点学科建设项目的资助。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
