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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3100-3108.
Prepublished online as a Blood First Edition Paper on December 21, 2004; DOI 10.1182/blood-2004-07-2826.
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HEMATOPOIESIS
Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment
Tsutomu Toki,
Fumiki Katsuoka,
Rika Kanezaki,
Gang Xu,
Hidekachi Kurotaki,
Jiying Sun,
Takuya Kamio,
Seiji Watanabe,
Satoru Tandai,
Kiminori Terui,
Soroku Yagihashi,
Norio Komatsu,
Kazuhiko Igarashi,
Masayuki Yamamoto, and
Etsuro Ito
From the Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan; Center for Tsukuba Advanced Research Alliance (TARA Center) and Japan Science and Technology Agency Exploratory Research for Advanced Technology (JST-ERATO) Environmental Response Project, University Tsukuba, Tsukuba, Japan; Department of Pathology, Hirosaki University School of Medicine, Hirosaki, Japan; Department of Anatomy, Hirosaki University School of Medicine, Hirosaki, Japan; Department of Biomedical Chemistry, Hiroshima University School of Medicine, Hiroshima, Japan; and Department of Hematology, Jichi Medical School, Tochigi, Japan.
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.
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