Jiying Sun1, Marjorie Brand1, Yukari Zenke1, Satoshi Tashiro1, Mark Groudine1, Kazuhiko Igarashi1
1Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Hiroshima 734-8551, Japan; and Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Tóm tắt
Small Maf proteins serve as dual-function transcription factors through an exchange of their heterodimerization partners. For example, as heterodimers with hematopoietic cell-specific p45 NF-E2 or NF-E2-related factors (Nrf), they activate the β-globin or antioxidative stress enzyme heme oxygenase 1 (HO-1) genes, respectively. In contrast, together with Bach1, they repress these same genes. However, the signals leading to this partner exchange are not known. Using chromatin immunoprecipitation assays in NIH 3T3 cells, we show that heme, an inducer of
ho-1
, promotes displacement of Bach1 from the MafK-occupied
ho-1
enhancers, which is followed by Nrf2 binding to these elements. Whereas histone H3 at the
ho-1
enhancers and promoter is hyperacetylated irrespective of gene activity, exposure of cells to heme results in
de novo
hyperacetylation and hypermethylation of histone H3 in the transcribed region. These data indicate that, under normal conditions, the chromatin structure of
ho-1
is in a preactivation state, but transcription is repressed by Bach1. Heme induces switching of Maf dimers, resulting in
ho-1
expression. Heme also promotes displacement of Bach1 from the β-globin locus control region without affecting MafK binding in murine erythroleukemia cells. Thus, heme functions as a signaling molecule for gene expression in higher eukaryotes.
