Function of transcription factors in hematopoietic differentiation

转录因子在造血分化中的作用

基本信息

批准号：
16390277
负责人：
NAKANO Toru
金额：
$ 9.15万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390277/
关键词：
cell differentiation stem cell hematopoiesis transcription factor embryonic stem cell reprograming GATA-1 Runx-1 造血システム

项目摘要

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.

通过承诺和成熟产生血细胞未成熟的造血细胞。基因靶向分析表明，该过程涉及各种转录因子。但是，这些因素的分子功能尚不清楚。在此螺柱中，使用从小鼠胚胎干细胞（ES细胞）到OP9基质细胞（OP9系统）上的血细胞的体外分化以及转录因子功能的丧失或获得的结合，例如GATA等因素的作用分析了-1，GATA-2，RUNX-1和FOG-1。所有检测的因素都表明它们在造血分化方面的功能取决于细胞衍射的背景。换句话说，在不同的分化阶段，单个转录因子和辅助因子的功能不同。例如，红细胞特异性转录因子GATA-1分别对于早期和晚期erthropoiesis的增殖和分化至关重要。一个值得注意的结果是GATA-1 NULL PRERERERYTHROMERBLASTS的自我更新和多部位分化能力。我们发现，在存在促红细胞生成素的情况下，GATA-1无蛋白细胞可以在OP9基质细胞上生存和增殖。此外，通过刺激粒细胞巨噬细胞刺激因子（GM-CSF）（GM-CSF）和白介素3（IL-3），从GATA-1无核细胞中诱导髓样细胞和肥大细胞，但是未能实现淋巴样分化。通过体内转移。因此，没有终端分化所需的转录因子活性，甚至相对成熟和犯人的细胞与其他谱系的分化能力连续增殖。该数据表明，GATA-1是将红斑祖细胞固定到红细胞谱系的关键转录因子。