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Elife. 2018 Feb 26;7. pii: e31656. doi: 10.7554/eLife.31656.

NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus.

Author information

Department of Chemistry, University of Memphis, Memphis, United States.
W Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, United States.
Department of Biological Sciences, University of Memphis, Memphis, United States.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States.
Contributed equally


Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude. In hepatocytes, activated NRF2 bound specific enhancer regions of the core clock repressor gene Cry2, increased Cry2 expression and repressed CLOCK/BMAL1-regulated E-box transcription. Together these data indicate that NRF2 and clock comprise an interlocking loop that integrates cellular redox signals into tissue-specific circadian timekeeping.


Nrf2; Redox; biochemistry; chemical biology; circadian rhythm; mouse; neuroscience

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