View the Current Issue

Article

  • The EMBO Journal (2002) 21, 5216 - 5224
  • doi:10.1093/emboj/cdf516

Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene

Jiying Sun1,2,8, Hideto Hoshino3,4,8, Kazuaki Takaku5, Osamu Nakajima6, Akihiko Muto1, Hiroshi Suzuki1, Satoshi Tashiro1, Satoru Takahashi3, Shigeki Shibahara2, Jawed Alam7, Makoto M. Taketo5, Masayuki Yamamoto3 and Kazuhiko Igarashi1

  1. Department of Biomedical Chemistry, Hiroshima University Graduate School of Biomedical Sciences, Kasumi 1-2-3, Hiroshima 734-8551, Japan
  2. Department of Molecular Biology, Tohoku University School of Medicine, Sendai, Japan
  3. Institute of Basic Medical Sciences and Center for Tsukuba Research Alliance, University of Tsukuba, Tsukuba, Japan
  4. Present address: Department of Biotechnology, Graduate School of Agriculture and LifeSciences, The University of Tokyo, Tokyo, Japan
  5. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  6. Research Laboratory for Molecular Genetics, Yamagata University, Yamagata, Japan
  7. Department of Molecular Genetics, Alton Ochsner Medical Foundation, LA 70121, USA
  8. J.Sun and H.Hoshino contributed equally to this work

Correspondence to:

Kazuhiko Igarashi, E-mail: igarak@hiroshima-u.ac.jp

Received 24 May 2002; Accepted 13 August 2002; Revised 16 July 2002

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 Bach1 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 Bach1 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.

  • Keywords:

    • BTB domain,
    • heme,
    • Maf,
    • transcription repression