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Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1.

Reichard JF, Motz GT, Puga A - Nucleic Acids Res. (2007)

Bottom Line: In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1.By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction.Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. john.reichard@childrens.harvard.edu

ABSTRACT
Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

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Induction of HMOX1 through the interplay of BACH1 and NRF2 with enhancer elements. (A) Binding of BACH1 (red ovals) at the E1 and E2 enhancer elements of HMOX1 in untreated control cells blocks NRF2 (blue ovals) binding and HMOX1 induction. Competition for ARE-binding elements between activated NRF2 and DNA-bound BACH1 is indicated by hypothetical rate constants representing stochastic binding (kon) and dissociation (koff) of NRF2. (B) Inactivation of BACH1 by hemin results in its removal from ARE motifs and elimination from the nucleus. Consequently, NRF2 can interact with exposed ARE enhancers to recruit RNA pol II (green oval) leading to high-level HMOX1 induction. (C) DNA-bound BACH1 blocks DNA binding of NRF2 despite its nuclear accumulation and prevents efficient HMOX1 induction. (D) Treatment with arsenite or co-treatment with hemin + MG132 results in BACH1 inactivation, nuclear accumulation and ARE binding of NRF2, and high-level HMOX1 induction.
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Figure 7: Induction of HMOX1 through the interplay of BACH1 and NRF2 with enhancer elements. (A) Binding of BACH1 (red ovals) at the E1 and E2 enhancer elements of HMOX1 in untreated control cells blocks NRF2 (blue ovals) binding and HMOX1 induction. Competition for ARE-binding elements between activated NRF2 and DNA-bound BACH1 is indicated by hypothetical rate constants representing stochastic binding (kon) and dissociation (koff) of NRF2. (B) Inactivation of BACH1 by hemin results in its removal from ARE motifs and elimination from the nucleus. Consequently, NRF2 can interact with exposed ARE enhancers to recruit RNA pol II (green oval) leading to high-level HMOX1 induction. (C) DNA-bound BACH1 blocks DNA binding of NRF2 despite its nuclear accumulation and prevents efficient HMOX1 induction. (D) Treatment with arsenite or co-treatment with hemin + MG132 results in BACH1 inactivation, nuclear accumulation and ARE binding of NRF2, and high-level HMOX1 induction.

Mentions: Based on the dynamic exchange of BACH1 and NRF2 we propose that in cells naïve to oxidative stress, BACH1 is bound to the ARE enhancer motifs preventing NRF2 from binding and thereby repressing transcription (Figure 7A). Hemin treatment triggers removal of BACH1 from HMOX1 enhancers thereby allowing NRF2 that is already present in the nucleus to interact with ARE motifs and elicit gene induction (Figure 7B). On the other hand, MG132 triggers NRF2 translocation to the nucleus but DNA-bound BACH1 blocks NRF2–ARE interactions to prevent gene induction (Figure 7C). The vast increase in the presence of nuclear NRF2 permits some increase in NRF2 binding to HMOX1 AREs but the presence of BACH1 maintains gene repression. Treatment with either arsenite or hemin plus MG132 triggers both the removal of BACH1 and the activation of NRF2, which can now freely bind vacant enhancer motifs (Figure 7D).Figure 7.


Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1.

Reichard JF, Motz GT, Puga A - Nucleic Acids Res. (2007)

Induction of HMOX1 through the interplay of BACH1 and NRF2 with enhancer elements. (A) Binding of BACH1 (red ovals) at the E1 and E2 enhancer elements of HMOX1 in untreated control cells blocks NRF2 (blue ovals) binding and HMOX1 induction. Competition for ARE-binding elements between activated NRF2 and DNA-bound BACH1 is indicated by hypothetical rate constants representing stochastic binding (kon) and dissociation (koff) of NRF2. (B) Inactivation of BACH1 by hemin results in its removal from ARE motifs and elimination from the nucleus. Consequently, NRF2 can interact with exposed ARE enhancers to recruit RNA pol II (green oval) leading to high-level HMOX1 induction. (C) DNA-bound BACH1 blocks DNA binding of NRF2 despite its nuclear accumulation and prevents efficient HMOX1 induction. (D) Treatment with arsenite or co-treatment with hemin + MG132 results in BACH1 inactivation, nuclear accumulation and ARE binding of NRF2, and high-level HMOX1 induction.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 7: Induction of HMOX1 through the interplay of BACH1 and NRF2 with enhancer elements. (A) Binding of BACH1 (red ovals) at the E1 and E2 enhancer elements of HMOX1 in untreated control cells blocks NRF2 (blue ovals) binding and HMOX1 induction. Competition for ARE-binding elements between activated NRF2 and DNA-bound BACH1 is indicated by hypothetical rate constants representing stochastic binding (kon) and dissociation (koff) of NRF2. (B) Inactivation of BACH1 by hemin results in its removal from ARE motifs and elimination from the nucleus. Consequently, NRF2 can interact with exposed ARE enhancers to recruit RNA pol II (green oval) leading to high-level HMOX1 induction. (C) DNA-bound BACH1 blocks DNA binding of NRF2 despite its nuclear accumulation and prevents efficient HMOX1 induction. (D) Treatment with arsenite or co-treatment with hemin + MG132 results in BACH1 inactivation, nuclear accumulation and ARE binding of NRF2, and high-level HMOX1 induction.
Mentions: Based on the dynamic exchange of BACH1 and NRF2 we propose that in cells naïve to oxidative stress, BACH1 is bound to the ARE enhancer motifs preventing NRF2 from binding and thereby repressing transcription (Figure 7A). Hemin treatment triggers removal of BACH1 from HMOX1 enhancers thereby allowing NRF2 that is already present in the nucleus to interact with ARE motifs and elicit gene induction (Figure 7B). On the other hand, MG132 triggers NRF2 translocation to the nucleus but DNA-bound BACH1 blocks NRF2–ARE interactions to prevent gene induction (Figure 7C). The vast increase in the presence of nuclear NRF2 permits some increase in NRF2 binding to HMOX1 AREs but the presence of BACH1 maintains gene repression. Treatment with either arsenite or hemin plus MG132 triggers both the removal of BACH1 and the activation of NRF2, which can now freely bind vacant enhancer motifs (Figure 7D).Figure 7.

Bottom Line: In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1.By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction.Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. john.reichard@childrens.harvard.edu

ABSTRACT
Oxidative stress activates the transcription factor NRF2, which in turn binds cis-acting antioxidant response element (ARE) enhancers and induces expression of protective antioxidant genes. In contrast, the transcriptional repressor BACH1 binds ARE-like enhancers in cells naïve to oxidative stress and antagonizes NRF2 binding until it becomes inactivated by pro-oxidants. Here, we describe the dynamic roles of BACH1 and NRF2 in the transcription of the heme oxygenase-1 (HMOX1) gene. HMOX1 induction, elicited by arsenite-mediated oxidative stress, follows inactivation of BACH1 and precedes activation of NRF2. BACH1 repression is dominant over NRF2-mediated HMOX1 transcription and inactivation of BACH1 is a prerequisite for HMOX1 induction. In contrast, thioredoxin reductase 1 (TXNRD1) is regulated by NRF2 but not by BACH1. By comparing the expression levels of HMOX1 with TXNRD1, we show that nuclear accumulation of NRF2 is not necessary for HMOX1 induction; rather, BACH1 inactivation permits NRF2 already present in the nucleus at low basal levels to bind the HMOX1 promoter and elicit HMOX1 induction. Thus, BACH1 confers an additional level of regulation to ARE-dependent genes that reveals a new dimension to the oxidative stress response.

Show MeSH
Related in: MedlinePlus