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J. Biol. Chem., Vol. 279, Issue 7, 5480-5487, February 13, 2004

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

Tsuyoshi Tahara, Jiying Sun, Katsuyuki Nakanishi, Masafumi Yamamoto, Hajime Mori, Takeshi Saito¶, Hiroyoshi Fujita¶, Kazuhiko Igarashi, and Shigeru Taketani||

From the Department of Biotechnology, Kyoto Institute of Technology, Kyoto 606-8585, the Department of Medical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8551, and ^¶Department of Environmental Biology, Hokkaido University School of Medicine, Sapporo 060-8638, Japan

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 -globin gene, mouse erythroleukemia (MEL) cells were cultured with succinylacetone (SA), a specific inhibitor of heme biosynthesis, and the level of -globin mRNA was examined. A marked decrease of -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 -globin mRNA. The heme-dependent expression of -globin is a transcriptional event since the expression of the human -globin gene promoter-reporter gene containing the microlocus control region (µLCR) 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 µLCR--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 µLCR activity, and this repressor activity was cancelled by treatment with hemin. The expression of a mutated Bach1 lacking heme-binding sites led to a loss in the heme responsiveness of the µLCR. Furthermore, chromatin immunoprecipitation experiments revealed that Bach1 bound to the MARE of HS2 increased by the treatment of MEL cells with SA, and this was cancelled by hemin. We propose that heme positively regulates the -globin gene expression by blocking the interaction of Bach1 with the MARE in the LCR.

Received for publication, March 18, 2003 , and in revised form, December 1, 2003.

^* This study was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan and from the Yamanouchi Foundation for Research on Metabolic Disorders The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 81-75-724-7789; Fax: 81-75-724-7760; E-mail: taketani{at}ipc.kit.ac.jp.

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