Disease relevance of Bach1

• Heme also promotes displacement of Bach1 from the beta-globin locus control region without affecting MafK binding in murine erythroleukemia cells [1].
• Myocardial infarction was markedly reduced in size by 48.4% in Bach1(-/-) mice [2].
• Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice [2].
• Bach1 may regulate gene expression in these cells during inflammation and atherogenesis [3].
• Furthermore, by using DNase I hypersensitivity assay, we demonstrate that simple chromatin condensations were not involved in the Bach1-mediated repression [4].

High impact information on Bach1

• These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression [5].
• While the cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion [5].
• Bach1 bound to the multiple Maf recognition elements (MAREs) of ho-1 enhancers with MafK in vitro and repressed their activity in vivo, while heme abrogated this repressor function of Bach1 by inhibiting its binding to the ho-1 enhancers [6].
• Thus, regulation of ho-1 involves a direct sensing of heme levels by Bach1 (by analogy to lac repressor sensitivity to lactose), generating a simple feedback loop whereby the substrate effects repressor-activator antagonism [6].
• Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1 [7].

Chemical compound and disease context of Bach1

• 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 [8].

Biological context of Bach1

• In mammalian cells, heme also functions as an intracellular regulator of gene expression by virtue of its ability to bind to Bach1, a transcription factor that functions in association with small Maf proteins [9].
• Interestingly, Bach1, a highly homologous protein, could not induce cell death, demonstrating the specificity for the apoptosis induction [10].
• The up-regulated phagocytic activity and reduced SMC proliferation of bach1-deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1 [3].
• Furthermore, in transfection studies we found that Bach1 repressed the enhancer activity of the LCR in a BTB/POZ domain-dependent manner [11].
• Bach1 possesses a basic leucine zipper (bZip) domain, as well as a BTB/POZ domain that has been shown to be involved in the regulation of chromatin structure [11].

Anatomical context of Bach1

• 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 [1].
• Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium [2].
• While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1(-/-) mice than in Bach1(+/+) mice [2].
• Heme positively regulates the expression of beta-globin at the locus control region via the transcriptional factor Bach1 in erythroid cells [8].
• These results strongly indicate that Bach1 and ARA70 have valuable roles at the onset of adipocyte differentiation [12].

Associations of Bach1 with chemical compounds

• 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 [8].
• Previous studies have shown that increased levels of heme and cadmium induce the nuclear export of Bach1, resulting in cytoplasmic accumulation [13].
• A novel splice variant of Nrf1 with a 411 bp deletion of the serine-rich region, resulting in an overall structure reminiscent of the BTB and CNC homology (Bach) proteins, was isolated from the corresponding DC18 cells [14].

Other interactions of Bach1

• Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network [1].
• Bach2 was induced upon neuronal differentiation of P19 embryonic carcinoma cells, while its related factor Bach1 did not show significant change [15].

Analytical, diagnostic and therapeutic context of Bach1

• Gene targeting experiments in mice revealed that, in the absence of Bach1, ho-1 became expressed constitutively at high levels in various tissues under normal physiological conditions [6].
• The DNA-binding activity of Bach1 as a MafK hetero-oligomer was markedly inhibited by heme in gel mobility shift assays [7].
• Sequence analysis of albumin protein revealed homology to the redox-regulated transcription factors Bach1 and 2, as well as cytoskeletal and molecular motor proteins [16].
• Immunofluorescence assays and Western blot analysis revealed that both Bach1 and Nrf2 localized in the cytoplasm and nucleus of the untreated cells [17].

References