Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene

Jiying Sun, Hideto Hoshino, Kazuaki Takaku, Osamu Nakajima, Akihiko Muto, Hiroshi Suzuki, Satoshi Tashiro, Satoru Takahashi, Shigeki Shibahara, Jawed Alam, Makoto M. Taketo, Masayuki Yamamoto, Kazuhiko Igarashi

Research output: Contribution to journalArticlepeer-review

429 Citations (Scopus)

Abstract

Heme oxygenase-1 (HO-1) protects cells from various insults including oxidative stress. Transcriptional activators, including the Nrf2/Maf heterodimer, have been the focus of studies on the inducible expression of ho-1. Here we show that a heme-binding factor, Bach1, is a critical physiological repressor of ho-1. 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 Bachl by inhibiting its binding to the ho-1 enhancers. 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. By analyzing bach1/nrf2 compound-deficient mice, we documented antagonistic activities of Bachl and Nrf2 in several tissues. Chromatin immunoprecipitation revealed that small Maf proteins participate in both repression and activation of ho-1. 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.

Original languageEnglish
Pages (from-to)5216-5224
Number of pages9
JournalEMBO Journal
Volume21
Issue number19
DOIs
Publication statusPublished - 2002 Oct 1

Keywords

  • BTB domain
  • Heme
  • Maf
  • Transcription repression

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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