Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.
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DOI：
10.1182/blood-2004-07-2826
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发表时间：
2005-04
期刊：
影响因子：
20.3
通讯作者：
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
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文献类型：
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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
核因子红细胞2 45 kDa亚基（p45）和BTB和CNC同源物1（Bach）转录因子都可以与一种小Maf蛋白形成二聚体，这些异二聚体与肌腱膜纤维肉瘤癌基因（Maf）识别元件（MARE）结合。已知MARE作为红系和巨核细胞基因的关键顺式调节元件。虽然p45-null突变小鼠和小maf复合突变小鼠的详细分析表明，这些因素都是血小板生成的关键，Bach 1的功能贡献和Bach 1和p45之间的关系或冗余在巨核细胞仍有待澄清。为了解决这些问题，我们产生了转基因小鼠品系，这些小鼠带有受加塔-1基因座造血调控结构域控制的人BACH 1 cDNA。转基因小鼠系表现出与巨核细胞成熟受损相关的显著血小板减少症，并且它们发展为骨髓纤维化。转基因小鼠巨核细胞前血小板形成减少，巨核细胞的众数倍性为2N，表明内有丝分裂受损。p45靶基因的转录被下调，我们确实发现BACH 1与巨核细胞中p45的靶基因之一血栓素合酶基因结合。因此，这些研究结果提供了证据，BACH 1作为一个转录抑制剂的调节MARE依赖的基因在巨核细胞。
Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeurotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of erythroid and megakaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bach1 and the relationship or redundancy between Bach1 and p45 in megakaryocytes remain to be clarified. To address these issues, we generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired maturation of the megakaryocytes, and they developed myelofibrosis. The megakaryocytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes. These findings thus provide evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megakaryocytes.