ROS regulates circadian rhythms by modulating Ezh2 interactions with clock proteins

Area of Science:

• Molecular Biology
• Chronobiology
• Oxidative Stress Research

Background:

• Accumulation of reactive oxygen species (ROS) and redox imbalance are linked to accelerated aging and diminished circadian rhythm amplitude.
• The precise molecular mechanisms by which ROS impact circadian rhythms are not well understood.
• Understanding these mechanisms is crucial for addressing age-related and circadian rhythm disorders.

Purpose of the Study:

• To elucidate the role of reactive oxygen species (ROS) in disrupting circadian rhythms.
• To identify key molecular players involved in ROS-mediated circadian disruption.
• To investigate the interaction between oxidative stress, EZH2, and the core circadian clock machinery.

Main Methods:

• Weighted gene co-expression network analysis (WGCNA) and machine learning (RF, LASSO, SVM) to identify key genes.
• Utilized zebrafish and human cell models to study circadian rhythm disruption.
• Employed genetic manipulation (ezh2 mutants, Morpholino, overexpression) and molecular assays (co-IP, ChIP, dual-luciferase reporter assays).

Main Results:

• ROS were confirmed to disrupt circadian rhythms in zebrafish and human cells, affecting behavior and clock gene expression.
• EZH2 was identified as a critical gene mediating the effects of ROS on circadian rhythms.
• EZH2 was shown to interact with the CLOCK-BMAL1 complex, regulating clock gene transcription under oxidative stress.

Conclusions:

• Reactive oxygen species disrupt circadian rhythms by modulating the interaction between EZH2 and the CLOCK-BMAL1 complex.
• This study reveals a novel molecular pathway linking oxidative stress to circadian rhythm dysfunction.
• Findings suggest EZH2 as a potential therapeutic target for age-related and circadian rhythm disorders.