GENETIC CONTROL OF HEMATOPOIETIC CELL DOFFERENTIATION

造血细胞分化的遗传控制

• 批准号: 09044255
• 负责人: IGARASHI Kazuhiko
• 金额: $ 3.65万
• 依托单位: Tohoku University (1998)University of Tsukuba (1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044255/
• 关键词: NF-E2; GATA; Bach; KNOCKOUT MOUSE; 血液細胞; 赤血球; 転写因子; 細胞分化

Hematopoiesis is a good model system for analyzing regulation of cell differentiation. Using this system, we tried to identify transcription factors that regulate cell differentiation. We analyzed function of NF-E2 and related factors, and accumulated novel as well as unexpected results. These findings should lead to understanding of molecular and genetic regulation of hematopoiesis.(1) To identify novel NF-E2-related transcription factors, we carried out further homology screening. As a result, we succeeded in identifying sixth member of the NF-E2-related factors which we named Nrf3. Its expression profile suggested that Nrf3 may regulate differentiation of hematopoietic cell differentiation. We are now carrying out gene disruption experiment using mice system, together with Prof.Engel.(2) By making nrf2-knockout mice and analyzing its phenotypic changes, we revealed that Nrf2 is a key essentail regulator of phase II de-toxifying system expression.(3) The BTB domain of Bach1 and Bach2 appears to be involved in regulation of chromatin structure. Using atomic force microscopy, we revealed that Bach1, and possible Bach2, function as a novel type of architectural transcription factor that mediate DNA loop formation. As such, Bach1 may be involved in regulation of the globin gene locus control region.

造血系统是分析细胞分化调控的良好模型系统。利用这个系统，我们试图识别调节细胞分化的转录因子。我们分析了NF-E2的功能和相关因素，并积累了新颖和意想不到的结果。这些发现将有助于理解造血的分子和遗传调控。(1)为了鉴定新的nf - e2相关转录因子，我们进行了进一步的同源性筛选。结果，我们成功地确定了nf - e2相关因子的第六个成员，我们将其命名为Nrf3。其表达谱提示Nrf3可能调控造血细胞的分化。我们正在和恩格尔教授一起进行小鼠系统的基因破坏实验。(2)通过构建Nrf2敲除小鼠并分析其表型变化，我们发现Nrf2是II期解毒系统表达的关键关键调控因子。(3) Bach1和Bach2的BTB结构域可能参与染色质结构的调控。利用原子力显微镜，我们发现Bach1和可能的Bach2作为一种新型的结构转录因子介导DNA环的形成。因此，Bach1可能参与珠蛋白基因位点控制区的调控。

项目成果

Nagai, T., Igarashi, K., Akasaka, J., Furuyama, K., Fujita, H., Hayashi, N., Yamamoto, M.and Sassa, S.: "Regulation of NF-E2 activity in erythroleukemia cell differentiation" J.Biol.Chem.273. 5358-5365 (1998)

Nagai, T.、Igarashi, K.、Akasaka, J.、Furuyama, K.、Fujita, H.、Hayashi, N.、Yamamoto, M. 和 Sassa, S.：“红白血病细胞中 NF-E2 活性的调节

Kobayashi, A., Ito, E., Toki, T., Kogame, K., Takahashi, S., Igarashi, K., Hayashi, N., and Yamamoto, M.: "Molecular cloning and functional characterization of a new Cap'n'collar family transcription factor Nrf3." J.Biol.Chem.274. 6443-6452 (1999)

Kobayashi, A.、Ito, E.、Toki, T.、Kogame, K.、Takahashi, S.、Igarashi, K.、Hayashi, N. 和 Yamamoto, M.：“新的分子克隆和功能表征

Muto,A.: "Identification of Bach2 as a B cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer" EMBO Journal. 17. 5734-5743 (1998)

Muto,A.：“鉴定 Bach2 作为小 Maf 蛋白的 B 细胞特异性伴侣，负向调节免疫球蛋白重链基因 3 增强子”EMBO 杂志。

Nagai, T: "Regulation of NF-E2 activity in erythroleukemia cell differentiation." Journal of Biological Chemistry. 273. 5358-5365 (1998)

Nagai, T：“红白血病细胞分化中 NF-E2 活性的调节。”

Muto, A.: "Identification of Bach2 as a B cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3'enhancer" EMBO Journal. 17. 5734-5743 (1998)

Muto, A.：“鉴定 Bach2 作为小 Maf 蛋白的 B 细胞特异性伴侣，负向调节免疫球蛋白重链基因 3 增强子”EMBO 杂志。