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

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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.