title: Heme-mediated inhibition of Bach1 regulates the liver specificity and transience of the Nrf2-dependent induction of zebrafish heme oxygenase 1.
abstract: The induction of the gene encoding heme oxygenase 1 (Hmox1, HO-1) by Nrf2 is unique compared with other Nrf2 targets. We previously showed that the Nrf2a-mediated induction of zebrafish hmox1a was liver specific and transient. We screened transcription factors that could repress the induction of hmox1a but not other Nrf2a targets and concluded that Bach1b was a prime candidate. In bach1b-knocked-down larvae, the induction of hmox1a was observed ectopically in nonliver tissues and persisted longer than normal fish, suggesting that Bach1 is the only regulator for both the liver-specific and transient induction of hmox1a. Co-knockdown of bach1b with its co-ortholog bach1a enhanced these effects. To determine why Bach1 could not repress the hmox1a induction in the liver, we analyzed the effects of a heme biosynthesis inhibitor, succinylacetone, and a heme precursor, hemin. Succinylacetone decreased the Nrf2a-mediated hmox1a induction, whereas pre-treatment with hemin caused ectopic induction of hmox1a in nonliver tissues, implying that the high heme levels in the liver may release the repressive activity of Bach1. Our results suggested that Bach1 regulates the liver specificity and transience of the Nrf2a-dependent induction of hmox1a and that heme mediates this regulation through Bach1 inhibition based on its level in each tissue.
authors.affiliation: Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fuse
authors.affiliation: Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.affiliation: Research Laboratory for Molecular Genetics, Yamagata University, Yamagata, 990-9585, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakajima
authors.affiliation: Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053898:Biosynthetic Pathways / Q000187:drug effects; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D006537:Heptanoates / Q000494:pharmacology; D007814:Larva / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009928:Organ Specificity; D015027:Zebrafish / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D006537:Heptanoates; D051267:NF-E2-Related Factor 2; D029961:Zebrafish Proteins; C000605842:bach1a protein, zebrafish; C000605844:bach1b protein, zebrafish; C495638:nfe2l2a protein, zebrafish; D006418:Heme; C020804:succinylacetone; D006427:Hemin; D051547:Heme Oxygenase-1; C000605843:heme oxygenase 1, zebrafish