NRF1,2,3 similarities and differences

The nuclear factor (erythroid 2)-like (NRF) transcription factors are a subset of Cap ‘n’ Collar transcription factors consisting of 3 members (NRF1, NRF2, and NRF3) that regulate the expression of genes containing antioxidant response elements (AREs) in their promoter regions. Although all NRF members regulate ARE-containing genes, each is associated with distinct roles. A comprehensive look at differential and overlapping DNA binding and transcriptional alterations has not been conducted. We performed ChIP-exo sequencing in conjunction with RNA sequencing to define the transcription targets of each NRF member. 31 genes were regulated by all three transcription factors: 27 genes were regulated similarly by all three members. Four genes were regulated differently by at least one member. We also found genes regulated by only one NRF member. 84 genes regulated by NRF1, 84 genes by NRF2, and 22 genes by NRF3. Analysis of ARE motifs in ChIP peaks revealed NRF2 prefers binding to AREs flanked by GC rich regions, while NRF1 prefers AT rich regions. Sequence predilection, likely in combination with upstream signaling events, determine which NRF members become active under which cellular context. Our analysis provides a comprehensive description of differential and overlapping gene regulation by the NRF1, NRF2, and NRF3.