Heme Positively Regulates the Expression of β-Globin at the Locus Control Region via the Transcriptional Factor Bach1 in Erythroid Cells

作者：Tsuyoshi Tahara, Jiying Sun, Katsuyuki Nakanishi, Masafumi Yamamoto, Hajime Mori, Takeshi Saito, Hiroyoshi Fujita, Kazuhiko Igarashi, Shigeru Taketani · 发表于：Journal of Biological Chemistry · 年份：2004 · DOI：10.1074/jbc.m302733200 · 被引用次数：126 · 研究领域：Erythrocyte Function and Pathophysiology、Heme Oxygenase-1 and Carbon Monoxide、Hemoglobinopathies and Related Disorders

The transcription factor Bach1 heterodimerizes with small Maf proteins to repress Maf recognition element (MARE)-dependent gene expression. The repressor activity of Bach1 is inhibited by the direct binding of heme. To investigate the involvement of Bach1 in the heme-dependent regulation of the expression of the beta-globin gene, mouse erythroleukemia (MEL) cells were cultured with succinylacetone (SA), a specific inhibitor of heme biosynthesis, and the level of beta-globin mRNA was examined. A marked decrease of beta-globin mRNA in SA-treated cells was observed, and this decrease was reversed by the addition of hemin. An iron chelator, desferrioxamine, also lowered the level of beta-globin mRNA. The heme-dependent expression of beta-globin is a transcriptional event since the expression of the human beta-globin gene promoter-reporter gene containing the microlocus control region (microLCR) was inhibited when human erythroleukemia K562 cells and MEL cells were cultured with SA. Hemin treatment restored the decrease in promoter activity caused by SA. The control of the microLCR-beta-globin promoter reporter gene by heme was dependent on DNase I-hypersensitive site 2 (HS2), which contains MARE. The MARE binding activity of Bach1 in K562 and MEL cells increased upon SA treatment, and the increase was diminished by the treatment with hemin. Transient expression of Bach1 suppressed the microLCR activity, and this repressor activity was cancelled by treatment with hemin. The expres...