11月22日,，Cell Research在線發(fā)表了中科院上海生科院生化與細(xì)胞所劉小龍研究組的研究成果“Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells”,，該工作揭示了轉(zhuǎn)錄因子KLF4對(duì)早期T細(xì)胞分化定向的調(diào)控機(jī)制,。
已有研究表明,，小鼠體細(xì)胞可以通過(guò)外源表達(dá)四個(gè)轉(zhuǎn)錄因子Klf4,、Oct4,、c-Myc,、Sox2而誘導(dǎo)生成多潛能干細(xì)胞（iPS）。這些轉(zhuǎn)錄因子通過(guò)調(diào)控細(xì)胞轉(zhuǎn)錄網(wǎng)絡(luò)來(lái)維持ES細(xì)胞的多潛能性和自我更新能力,。但是,，到目前為止仍然不夠清楚的是，這四個(gè)轉(zhuǎn)錄因子在成體干細(xì)胞以及其向特異的細(xì)胞譜系分化時(shí)是否具有功能,。
最近劉小龍研究組的博士研究生溫曉敏等研究發(fā)現(xiàn),，在造血干細(xì)胞（HSC）分化為T細(xì)胞的過(guò)程中Klf4的表達(dá)發(fā)生特異變化，在向T細(xì)胞分化前持續(xù)表達(dá),，但是在向T細(xì)胞分化時(shí)Klf4表達(dá)則被關(guān)閉,。在胸腺細(xì)胞中強(qiáng)制表達(dá)Klf4會(huì)嚴(yán)重影響DN2到DN3的分化進(jìn)程，而此時(shí)正好是決定多潛能的胸腺祖先細(xì)胞是否最終定向分化為T細(xì)胞的關(guān)鍵時(shí)刻,。強(qiáng)制表達(dá)Klf4會(huì)影響眾多T細(xì)胞分化關(guān)鍵調(diào)控因子的表達(dá),，包括胸腺微環(huán)境信號(hào)分子（IL-7Ra）、Notch靶標(biāo)（Deltex1）和轉(zhuǎn)錄調(diào)控因子（Bcl11a,、SpiB,、Id1）等。強(qiáng)制表達(dá)Klf4還會(huì)影響TCRb基因的DNA重排以及胸腺細(xì)胞的存活,，但是僅引入TCR轉(zhuǎn)基因并不能彌補(bǔ)其造成的分化缺陷,。而通過(guò)恢復(fù)IL-7Ra的表達(dá)則能在一定程度上彌補(bǔ)在Klf4轉(zhuǎn)基因鼠中存在的DN1-DN2 和DN2-DN3分化缺陷,。該研究不僅揭示下調(diào)Klf4表達(dá)對(duì)于T細(xì)胞的早期分化定向極其重要,，同時(shí)也拓展了對(duì)于參與重編程的這四個(gè)轉(zhuǎn)錄因子在細(xì)胞分化過(guò)程中所具有特定功能的理解。
劉小龍研究組的研究工作得到了國(guó)家自然科學(xué)基金委,，科技部和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi: 10.1038/cr.2011.183
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Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells
Xiaomin Wen, Haifeng Liu, Gang Xiao and Xiaolong Liu
The roles of the reprogramming factors Oct4, Sox2, c-Myc and Klf4 in early T cell development are incompletely defined. Here, we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors (ETPs) differentiate into T cells. Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2-to-DN3 transition when T cell lineage commitment occurs and affected the transcription of a variety of genes with crucial functions in early T cell development, including genes involved in microenvironmental signaling (IL-7Rα), Notch target genes (Deltex1), and essential T cell lineage regulatory or inhibitory genes (Bcl11a, SpiB, and Id1). The survival of thymocytes and the rearrangement at the Tcrb locus were impaired in the presence of enforced Klf4 expression. The defects in the DN1-to-DN2 and DN2-to-DN3 transitions in Klf4 transgenic mice could not be rescued by the introduction of a TCR transgene, but was partially rescued by restoring the expression of IL-7Rα. Thus, our data indicate that the downregulation of Klf4 is a prerequisite for T cell lineage commitment.
