REGγ regulates circadian clock by modulating BMAL1 protein stability

Area of Science:

• * Chronobiology and molecular mechanisms of circadian rhythms.
• * Proteasome-mediated protein degradation.
• * Mammalian gene expression regulation.

Background:

• * Circadian rhythms are endogenous biological processes synchronized with the 24-hour light-dark cycle.
• * These rhythms regulate gene expression to help organisms adapt to environmental periodicity.
• * The precise mechanisms by which circadian rhythms propagate through cells and control physiology are not fully understood.

Purpose of the Study:

• * To investigate the role of REGγ in regulating the mammalian circadian clock.
• * To elucidate the molecular mechanism by which REGγ influences circadian gene expression.
• * To determine the impact of REGγ deficiency on circadian behavior and physiology.

Main Methods:

• * Comparative analysis of circadian behavior in wild-type (WT) and REGγ knockout (KO) mice.
• * Quantification of circadian gene and protein expression in mouse suprachiasmatic nucleus (SCN) and cultured cells.
• * Investigation of REGγ's interaction with BMAL1 using proteasome degradation assays and gene silencing.

Main Results:

• * REGγ KO mice exhibit altered circadian period, wheel activity, and light-induced phase delay responses.
• * Circadian gene and protein levels (Per1, Per2, Bmal1) are elevated in REGγ KO mice and cells.
• * REGγ directly degrades BMAL1 via an ATP/ubiquitin-independent proteasome pathway, influencing Per1 and Per2 rhythms.

Conclusions:

• * REGγ acts as a novel rheostat for circadian rhythms, modulating Per1 and Per2 levels.
• * REGγ's function is mediated through the proteasomal degradation of BMAL1.
• * This study identifies REGγ as a key factor in maintaining circadian rhythm stability and physiological timing.