Department of Medical Biochemistry, Tohoku Medical Megabank Organization, Sendai, 980-8575, Japan.
Nucleic Acids Res. 2012 Nov 1;40(20):10228-39. doi: 10.1093/nar/gks827. Epub 2012 Sep 10.
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.
核因子红细胞 2 相关因子 2（Nrf2）是一种关键的转录因子，对于细胞抵抗氧化应激和外来物质的损伤至关重要。Nrf2 与小 Maf（sMaf）蛋白形成异二聚体，并与抗氧化反应元件（AREs）结合，激活一系列细胞保护基因。然而，Nrf2-sMaf 异二聚体在全基因组范围内对 ARE 依赖性基因调控的贡献程度仍不清楚。我们进行了染色质免疫沉淀结合高通量测序，并在全基因组范围内鉴定了 Nrf2 和 MafG 的结合位点。与仅由 Nrf2 占据的位点相比，许多由 Nrf2 和 MafG 共同占据的位点表现出高富集，并位于物种保守的基因组区域。在回收的 Nrf2-MafG 结合位点中，ARE 基序显著富集，但在未显示 MafG 结合的 Nrf2 结合位点中则没有。大多数 Nrf2 调节的细胞保护基因位于 Nrf2-MafG 结合位点附近。此外，调节葡萄糖代谢和几种氨基酸转运体的序列被鉴定为 Nrf2-MafG 靶基因，这表明 Nrf2-MafG 异二聚体在应激反应中具有多种作用。这些数据清楚地支持了这样一种观点，即 Nrf2-sMaf 异二聚体是通过相关的 ARE 调节参与细胞保护和代谢功能各个方面的基因的复合物。
