title: Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks.
abstract: NF-E2-related factor 2 (Nrf2) is a key transcription factor that is critical for cellular defense against oxidative and xenobiotic insults. Nrf2 heterodimerizes with small Maf (sMaf) proteins and binds to antioxidant response elements (AREs) to activate a battery of cytoprotective genes. However, it remains unclear to what extent the Nrf2-sMaf heterodimers contribute to ARE-dependent gene regulation on a genome-wide scale. We performed chromatin immunoprecipitation coupled with high-throughput sequencing and identified the binding sites of Nrf2 and MafG throughout the genome. Compared to sites occupied by Nrf2 alone, many sites co-occupied by Nrf2 and MafG exhibit high enrichment and are located in species-conserved genomic regions. The ARE motifs were significantly enriched among the recovered Nrf2-MafG-binding sites but not among the Nrf2-binding sites that did not display MafG binding. The majority of the Nrf2-regulated cytoprotective genes were found in the vicinity of Nrf2-MafG-binding sites. Additionally, sequences that regulate glucose metabolism and several amino acid transporters were identified as Nrf2-MafG target genes, suggesting diverse roles for the Nrf2-MafG heterodimer in stress response. These data clearly support the notion that Nrf2-sMaf heterodimers are complexes that regulate batteries of genes involved in various aspects of cytoprotective and metabolic functions through associated AREs.
authors.affiliation: Department of Medical Biochemistry, Tohoku Medical Megabank Organization, Sendai, 980-8575, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hirotsu
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks; D016678:Genome; D051259:MafG Transcription Factor / Q000235:genetics / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements
chemical_list: D000975:Antioxidants; D051259:MafG Transcription Factor; C491247:Mafg protein, mouse; D008298:Maleates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012097:Repressor Proteins; D009249:NADP; C014476:diethyl maleate