The differential regulation of target genes by transcription factor BACH 1 in erythroid and megakaryocytic cells.

红细胞和巨核细胞中转录因子 BACH 1 对靶基因的差异调节。

• 批准号: 17591066
• 负责人: TOKI Tsutomu
• 金额: $ 2.37万
• 依托单位: Hirosaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591066/
• 关键词: Transcription factor; Megakaryocyte; BACH1; NF-E2; Down's syndrome

ObjectApproximately 10% of newborn babies with Down's syndrome (DS) are born with a leukemoid reaction commonly called transient myeloproliferative disorder (TMD). A portion of TMD patients will develop malignant acute megakaryoblastic leukemia (AMKL) during their first 4 years of life. The human BACH1 gene is localized to chromosome 21 within the potential DS-associated gene region. Objects in this research are as follows : First, finding novel target genes of the transcription factor BACH1. Second, disclosing the mechanism of the transcriptional regulation by BACH1 in erythroid or megakaryocytic cells. Third, investigating the contribution of BACH1 gene in developing TMD and AMKL in DS patients.ResultsWe established the transgenic (Tg) mice expressing human BACH1 gene in erythroid and megakaryocytic cells. We succeeded in culture of megakaryocytes in vitro using the fetal liver cells in the medium containing TPO. Next, we profiled the gene expression of erythroid and megakaryocytic cells derived from BACH1 Tg mice and wild littermates by micro array analysis using RNA extracted from cultured megakaryocytes and Ter119 positive cells. We confirmed the BACH1 target genes previously reported was regressed in megakaryocytes of BACH1 Tg mice. Mechanism of transcriptional regulation in novel target genes is being investigated. We found the some of BACH1 target genes were differentially regulated by BACH1 in erythroid and megakaryocytic cells. We are investigating the binding of BACH1 factor in the regulatory elements in these genes. We also succeeded in transducing the BACH1 gene to hematopoietic cell lines by retrovirus infection and analyzed the function of BACH1 in vitro experimetal systems.

大约10%的唐氏综合征（DS）新生儿出生时伴有一种通常称为短暂性骨髓增生性疾病（TMD）的类白血病反应。一部分TMD患者在生命的头4年将发展为恶性急性巨核母细胞白血病（AMKL）。人类BACH1基因定位于21号染色体内潜在的ds相关基因区域。本研究的目的如下：一是寻找新的转录因子BACH1的靶基因。第二，揭示BACH1在红细胞或巨核细胞中的转录调控机制。第三，探讨BACH1基因在DS患者TMD和AMKL发生中的作用。结果在红细胞和巨核细胞中建立了表达人BACH1基因的转基因（Tg）小鼠。我们成功地在含TPO的培养基中利用胎儿肝细胞体外培养巨核细胞。接下来，我们利用从培养的巨核细胞和Ter119阳性细胞中提取的RNA，通过微阵列分析分析了BACH1 Tg小鼠和野生幼崽的红细胞和巨核细胞的基因表达。我们证实了先前报道的BACH1靶基因在BACH1 Tg小鼠的巨核细胞中出现了倒退。新的靶基因的转录调控机制正在研究中。我们发现BACH1靶基因在红细胞和巨核细胞中受到BACH1的不同调控。我们正在研究BACH1因子在这些基因调控元件中的结合。我们还成功地通过逆转录病毒感染将BACH1基因转导到造血细胞系中，并在体外实验系统中分析了BACH1的功能。

项目成果

Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.

• DOI: 10.1182/blood-2004-07-2826
• 发表时间: 2005-04
• 期刊: Blood
• 影响因子: 20.3
• 作者: T. Toki;F. Katsuoka;Rika Kanezaki;Gang Xu;H. Kurotaki;Jiying Sun;T. Kamio;Seiji Watanabe;S. Tandai;K. Terui;S. Yagihashi;N. Komatsu;K. Igarashi;Masayuki Yamamoto;E. Ito