Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.
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.
Toki
Tsutomu
T
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Aomori, 036-8563 Japan.
Katsuoka
Fumiki
F
Kanezaki
Rika
R
Xu
Gang
G
Kurotaki
Hidekachi
H
Sun
Jiying
J
Kamio
Takuya
T
Watanabe
Seiji
S
Tandai
Satoru
S
Terui
Kiminori
K
Yagihashi
Soroku
S
Komatsu
Norio
N
Igarashi
Kazuhiko
K
Yamamoto
Masayuki
M
Ito
Etsuro
E
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000502:physiology; D050981:Erythroid-Specific DNA-Binding Factors; D051856:Fanconi Anemia Complementation Group Proteins; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D006801:Humans; D008533:Megakaryocytes / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D050984:NF-E2 Transcription Factor, p45 Subunit; D013921:Thrombocytopenia / Q000473:pathology / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051856:Fanconi Anemia Complementation Group Proteins; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D050984:NF-E2 Transcription Factor, p45 Subunit; D014157:Transcription Factors