Many cellular challenges ? chemical, metabolic, and physical ? generate reactive oxygen species (ROS), which have the potential to damage macromolecules including proteins, lipids, and nucleic acids. Members of the Cap-n-Collar (CNC) transcription factor family, including NRF2, regulate antioxidant gene expression and mitigate ROS-mediated damage. These opposing oxidant and antioxidant forces must be precisely balanced: too little NRF2 and excess ROS cause cell damage and mutation, whereas too much NRF2 gives cells a dangerous proliferative advantage. To fully understand the mechanistic implications of NRF2 activation we need a comprehensive view of its regulatory network, yet surprisingly little is known about the global reach of NRF2's regulatory activity and how it integrates with additional stress-responsive transcription factors. We will use a combination of hypothesis-driven genomics and focused biological validation experiments to provide both systems level and mechanistic insights into the NRF2 regulatory network and consequences of its activation. Importantly, this work will also address issues regarding the general principles of transcriptional regulatory precision, including: (1) how transcription factor DNA binding properties and combinatorial transcription factor interactions integrate to drive graded versus switch-like gene expression, (2) the dynamics and cell-type specificity of rapid transcriptional reprogramming in human cells, (3) how variation in cis- regulatory DNA is functionally linked to disease risk, and (4) the mechanisms of cell autonomous and non- autonomous regulatory network propagation. These are relevant issues for all transcriptional regulators, so the knowledge gained in the context of NRF2-mediated gene regulation will also extend to additional transcription factor families.

Public Health Relevance

Public Health Relevance: Oxidative stress, which has the potential to damage all classes of macromolecules, is an early and ongoing contributor to many chronic diseases, from cancer to neurodegenerative disease. The studies described here will use cutting edge genomic and molecular methods to identify the mechanisms by which cells respond to and recover from oxidative stress; this knowledge will provide a framework for understanding the links between cell oxidative stress and chronic disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM119553-05
Application #
9924553
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gaillard, Shawn R
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Levings, Daniel C; Wang, Xuting; Kohlhase, Derek et al. (2018) A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations. Redox Biol 19:235-249
Wang, Liangjun; Joshi, Preeti; Miller, Ellen L et al. (2018) A Role for Monomethylation of Histone H3-K27 in Gene Activity in Drosophila. Genetics 208:1023-1036
Lacher, Sarah E; Alazizi, Adnan; Wang, Xuting et al. (2018) A hypermorphic antioxidant response element is associated with increased MS4A6A expression and Alzheimer's disease. Redox Biol 14:686-693
Lacher, Sarah E; Slattery, Matthew (2016) Gene regulatory effects of disease-associated variation in the NRF2 network. Curr Opin Toxicol 1:71-79