Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network

Abstract

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 ␤-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 ␤-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.

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

“…GFP-GPI is expressed under a cytomegalovirus promoter whose activity can be enhanced by histone acetylation or demethylation (33). Given that hemin can regulate both histone acetylation and methylation (34), the increase of GFP-GPI on the cell surface could be due to increased expression, which was confirmed by a Western blot assay on total cell FIGURE 3. Reduction of cell surface PrP C with hemin treatment.…”

DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

“…In contrast, it is known that the Bach 1͞hemin interaction relieves Bach 1 inhibition of Maf͞Nrf2 interactions with MARE͞ARE (5Ј-TGAC͞GTCA-3Ј) DNA sequences (Fig. 1 A) to enhance transcription (35), as shown for QR (17) and heme oxygenase 1 (35,37), where the hemin response is comparable to ferritin-L (Figs. 2 and 4).…”

“…Direct binding of hemin to the DNA and mRNA repressors is a possible mechanism of the enhanced hemin effects when both DNA and mRNA regulators are present. Hemin is known to bind to both IRP 1 and IRP 2, the ferritin-L mRNA repressors, and Bach 1, a DNA transcription repressor for MARE͞ARE genes (33)(34)(35). Little is known about the molecular effects of hemin binding to IRP proteins, other than changing protein stability (33,36).…”

Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway

“…10). Furthermore, the more distal ARE probably has a propensity for Maf homodimerization according to a sequence analysis of this element, 50 which suggests that this ARE could potentially negatively regulate Mrp2. 51 For Mrp3, only the ARE that was 9919 bp upstream of the translational start site showed Nrf2 binding.…”