The NRF2/sMAF protein complex regulates the oxidative stress response by occupying cis-acting enhancers containing an antioxidant response element (ARE). Integrating genome-wide maps of NRF2/sMAF occupancy with disease-susceptibility loci, we discovered eight polymorphic AREs linked to 14 highly ranked disease-risk SNPs in individuals of European ancestry. Among these SNPs was rs242561, located within a regulatory region of the MAPT gene (encoding microtubule-associated protein Tau). It was consistently occupied by NRF2/sMAF in multiple experiments and its strong-binding allele associated with higher mRNA levels in cell lines and human brain tissue. Induction of MAPT transcription by NRF2 was confirmed using a human neuroblastoma cell line and a Nrf2-deficient mouse model. Most importantly, rs242561 displayed complete linkage disequilibrium with a highly protective allele identified in multiple GWASs of progressive supranuclear palsy, Parkinson's disease, and corticobasal degeneration. These observations suggest a potential role for NRF2/sMAF in tauopathies and a possible role for NRF2 pathway activators in disease prevention.
Bibliographical noteFunding Information:
This work was funded by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH (projects: Z01ES100475 and Z01ES46008), the University of Minnesota Foundation (to M.S.), and the Ludwig Institute for Cancer Research (to G.L.B.). The authors would like to acknowledge Dr. Shuangshuang Dai for Linux computing support; NIEHS Epigenomics Core; NIEHS Animal Facility Core; and Dr. Jean Harry, NIEHS, for technical advice and useful comments on the manuscript.