Hydrogen peroxide modulates clock gene expression via PRX2-STAT3-REV-ERBα/β pathway

Area of Science:

• Biochemistry
• Molecular Biology
• Chronobiology

Background:

• Circadian rhythms, governed by transcriptional/translational feedback loops (TTFLs), are fundamental to life.
• Oxidative stress is implicated in aging and diseases like cancer and Alzheimer's.
• The precise mechanisms by which oxidants affect circadian gene expression remain unclear.

Purpose of the Study:

• To investigate the impact of hydrogen peroxide (H₂O₂), a key oxidative stress mediator, on circadian gene expression.
• To elucidate the molecular pathways through which H₂O₂ influences biological rhythms.

Main Methods:

• Utilized NIH3T3 cells to examine protein expression of circadian genes (Clock, Bmal1, Per1/2, Cry1/2) upon H₂O₂ treatment.
• Assessed the modulation of Bmal1-luciferase rhythm by H₂O₂ through specific nuclear receptors.
• Investigated the PRX2-STAT3-REV-ERBα/β pathway in response to H₂O₂.

Main Results:

• Hydrogen peroxide (H₂O₂) significantly upregulated the protein expression of Clock, Bmal1, Per1/2, and Cry1/2.
• H₂O₂ altered the circadian rhythm of Bmal1-luciferase, involving RORα, REV-ERBα (NR1D1), and REV-ERBβ (NR1D2).
• A novel regulatory pathway, PRX2-STAT3-REV-ERBα/β, was identified as a mechanism for H₂O₂-induced circadian rhythm modulation.

Conclusions:

• Oxidative stress, specifically H₂O₂, directly influences the core circadian clock gene machinery.
• The PRX2-STAT3-REV-ERBα/β pathway represents an accessory loop that interacts with TTFLs, providing a new understanding of circadian rhythm regulation under oxidative stress.