Function of transcription factors in hematopoietic differentiation

血细胞是由未成熟的造血细胞通过承诺和成熟产生的。基因靶向分析表明，多种转录因子参与了这一过程。然而，这些因子的分子功能尚不清楚。本研究结合OP9基质细胞（OP9系统）上小鼠胚胎干细胞（ES细胞）向血细胞的体外分化，以及转录因子功能的丧失或获得，分析了GATA-1、GATA-2、Runx-1、fog1等因子的作用。结果表明，这些因子对造血分化的作用取决于细胞分化的环境。也就是说，个体转录因子和辅助因子在不同分化阶段的功能是不同的。例如，红系特异性转录因子GATA-1在早期和晚期的造血过程中分别是增殖和分化所必需的。一个值得注意的结果是GATA-1缺失的原红细胞的自我更新和多谱系分化能力。我们发现，在促红细胞生成素存在的情况下，gata -1缺失的原红细胞可以在OP9基质细胞上存活和增殖。此外，在粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-3 （IL-3）的刺激下，gata -1缺失的原红细胞分别诱导出髓细胞和肥大细胞，但体内转移无法实现淋巴细胞分化。因此，如果没有末端分化所需的转录因子的活性，即使是相对成熟和承诺的细胞也会不断增殖，并具有向其他谱系的分化能力。这些数据表明GATA-1是将红系祖细胞固定到红系谱系的关键转录因子。

Blood cells are produced immature hematopoietic cells through commitment and maturation. Gene targeting analyses have revealed that various transcription factors are involved in the process. However, molecular functions of the factors remain unclear. In this stud, using the combination of in vitro differentiation from mouse embryonic stem cells (ES cells) to blood cells on OP9 stroma cells (OP9 system), and loss or gain of function of the transcription factors, roles of the factors such as GATA-1, GATA-2, Runx-1, and FOG-1 were analyzed.All of the factors examined showed that their functions on hematopoietic differentiation was dependent on the context of the cell diffrentiation. In other words, individual transcription factors and co-factors' function was different at different differentiation stages. For example, erythroid specific transcription factor, GATA-1, was essential for proliferation and differentiation at early and late erthropoiesis, respectively.One notable result is the self-renewal and multi-lineage differentiation ability of GATA-1 null proerythroblasts. We found that GATA-1-null proerythroblasts could survive and proliferate on OP9 stroma cells in the presence of erythropoietin. Furthermore, myeloid and mast cells were induced from the GATA-1-null proerythroblasts by the stimulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), respectively, but lymphoid differentiation was not achieved by in vivo transfer. Thus, without activity of the transcription factor required for terminal differentiation, even relatively mature and committed cells proliferate continuously with the differentiation capacity to other lineages. This data suggest that GATA-1 is a critical transcription factor to fix erythroid progenitors to the erythroid lineage.