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

Tahara Tsuyoshi

Sun Jiying

Nakanishi Katsuyuki

Yamamoto Masafumi

Mori Hajime

Fujita Hiroyoshi

Igarashi Kazuhiko

Taketani Shigeru

Biochemical and Biophysical Research Communications

The transcription factor Bach1 hetero-dimerizes 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 the investigate involvement of Bach1 in the heme-dependent regulation of the expression of the β-globin gene, mouse erythroleukemia (MEL) cells were cultured with succinylacetone (SA), a specific inhibitor of heme biosynthesis, and the level of β-globin mRNA was examined. A marked decrease of β-globin mRNAin SA-treated cells was observed, and was reversed by the addition of hemin. An iron chelator, desferrioxamine, also lowered the level of β-globin mRNA. The heme-dependent expression of β-globin is a transcriptional event since the expression of the human β-globin gene promoter-reporter gene containing the micro-locus 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-β-globin promoter reporter gene by heme was dependent on DNase I-hypersensitive site 2 which contains MARE. 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. 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. Furthermore, during erythroid differentiation of MEL cells, the MARE-binding activity of Bach1 decreased while simultaneously, the NF-E2 activity increased. Wepropose that heme positively regulates the β-globin gene expression by blocking the interaction of Bach1 with the MAREin the LCR in erythoid cells.

Medical sciences [ 490 ]

eng

Elsevier

Copyright (c) 2004 Elsevier Inc.

[ISSN] 0006-291X

[DOI] 10.1016/j.bbrc.2004.09.022

[NCID] AA00564395

[DOI] http://dx.doi.org/10.1016/j.bbrc.2004.09.022