Abstract
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.
Highlights
Circadian clocks are an evolutionarily conserved timekeeping mechanism that allows organisms to anticipate and adapt their behavior, physiology, and biochemistry to predictable changes in their environment
Nrf2 deficiency did not alter the down-regulation of Bmal1, Cry1, or E4bp4, suggesting their independence of NF-E2 related-factor 2 (NRF2) and that the circadian network effect did not transmit to receptor response elements (ROREs)-mediated transcription
We evaluated whether the effects of D3T on circadian gene expression observed in vivo manifested in alterations in circadian function in vitro and whether those potential alterations were dependent on NRF2
Summary
Circadian clocks are an evolutionarily conserved timekeeping mechanism that allows organisms to anticipate and adapt their behavior, physiology, and biochemistry to predictable changes in their environment. A combination of experiments revealed that mouse liver cells need NRF2 to maintain a normal circadian rhythm, and a closer inspection of the liver cells revealed that NRF2 attaches to part of the gene for a clock protein called CRY2 This enhances the production of this protein, which in turn, switches CLOCK and BMAL1 off. In this way, NRF2 links metabolism signals to the ticking of the circadian clock. CLOCK/BMAL1-dependent Nrf regulation gives rise to diurnal patterns in NRF2 signaling, which underlies the rhythmic expression of antioxidant and metabolic enzymes as well as NADPH reducing equivalents and glutathione biosynthesis (Xu et al, 2012). We report the effects of NRF2 gain- and loss-of-function on circadian gene expression and rhythmicity, elaborating the coupling of NRF2 and clock and the role of NRF2 to integrate cellular redox status into timekeeping
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
