Beyond antioxidant genes in the ancient Nrf2 regulatory network
Section snippets
Chemicals and materials
d,l-Sulforaphane (SFN) was purchased from MP Biomedicals (Santa Ana, CA, USA) or Calbiochem/Millipore (Billerica, MA, USA) and ethyl-7-chloro-4-hydroxy-8-methylquinoline-3-carboxylate (AI-1) was purchased from Calbiochem/Millipore. Luperox (tert-butylhydroperoxide solution; TBOOH) was purchased from Sigma–Aldrich Chemical Co. (St. Louis, MO, USA). Stock solutions of all test compounds were prepared in dimethyl sulfoxide (DMSO) and stored at −20 °C. FuGENE HD transfection reagent was purchased
Overview of Cnc/Nrf2 genome-wide binding in Drosophila
To get a genome-wide view of the Cnc/Nrf2 regulatory network in Drosophila, we performed ChIP-seq using an antibody against the C-terminal region of Cnc/Nrf2 that recognizes all Cnc isoforms (Fig. 1B). Chromatin was isolated from embryos (16–24 h after egg laying), white prepupae (at the transition between larval and pupal stages), or 2- to 3-day-old adults (male or female). Although it is a stress-responsive transcription factor, CncC—the Nrf2 ortholog—also regulates cytoprotective genes under
Conclusion
Together, these data demonstrate that the Keap1–Nrf2–MAF regulatory axis is strongly conserved from D. melanogaster to humans, even at the level of network structure. The regulatory reach of Nrf2 clearly extends well beyond antioxidant genes, covering metabolic genes, proteostasis genes, autoregulatory pathways, and more; this property of the Nrf2 network is also an ancient one. Importantly, because Nrf2 targets a variety of distinct gene batteries, it is also likely that Nrf2 employs more than
Acknowledgments
The authors thank Evan Odean (University of Minnesota), Lijia Ma (University of Chicago), Anshul Kundaje (Stanford), and Katherine Harris (SwitchGear Genomics) for technical assistance. This work was supported by funding from the University of Minnesota Foundation (M.S.) and the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health (Z01-ES-100475 and ES065079 to D.A.B.).
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