11月22日,，Cell Research在線發(fā)表了中科院上海生科院生化與細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對早期T細胞分化定向的調(diào)控機制。
已有研究表明,，小鼠體細胞可以通過外源表達四個轉(zhuǎn)錄因子Klf4,、Oct4,、c-Myc、Sox2而誘導(dǎo)生成多潛能干細胞（iPS）,。這些轉(zhuǎn)錄因子通過調(diào)控細胞轉(zhuǎn)錄網(wǎng)絡(luò)來維持ES細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,，這四個轉(zhuǎn)錄因子在成體干細胞以及其向特異的細胞譜系分化時是否具有功能,。
最近劉小龍研究組的博士研究生溫曉敏等研究發(fā)現(xiàn)，在造血干細胞（HSC）分化為T細胞的過程中Klf4的表達發(fā)生特異變化,，在向T細胞分化前持續(xù)表達,，但是在向T細胞分化時Klf4表達則被關(guān)閉。在胸腺細胞中強制表達Klf4會嚴重影響DN2到DN3的分化進程,，而此時正好是決定多潛能的胸腺祖先細胞是否最終定向分化為T細胞的關(guān)鍵時刻,。強制表達Klf4會影響眾多T細胞分化關(guān)鍵調(diào)控因子的表達，包括胸腺微環(huán)境信號分子（IL-7Ra）,、Notch靶標（Deltex1）和轉(zhuǎn)錄調(diào)控因子（Bcl11a,、SpiB、Id1）等,。強制表達Klf4還會影響TCRb基因的DNA重排以及胸腺細胞的存活,，但是僅引入TCR轉(zhuǎn)基因并不能彌補其造成的分化缺陷。而通過恢復(fù)IL-7Ra的表達則能在一定程度上彌補在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表達對于T細胞的早期分化定向極其重要,，同時也拓展了對于參與重編程的這四個轉(zhuǎn)錄因子在細胞分化過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家自然科學(xué)基金委,，科技部和上海市科委的經(jīng)費支持,。（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.
