Heme oxygenase-1 induction by NRF2 requires inactivation of the transcriptional repressor BACH1.
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.
Reichard
John F
JF
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati, Cincinnati, OH 45267-0056, USA. john.reichard@childrens.harvard.edu
Motz
Gregory T
GT
Puga
Alvaro
A
D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D051856:Fanconi Anemia Complementation Group Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020218:Response Elements; D015533:Transcriptional Activation
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051267:NF-E2-Related Factor 2; D012097:Repressor Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1