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Published on: September 17, 2016
Interaction of MAGED1 with nuclear receptors affects circadian clock function
Xiaohan Wang1, Jing Tang, Lijuan Xing
1MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Pukou District, Nanjing, China.
Abstract:
The circadian clock has a central role in physiological adaption and anticipation of day/night changes. In a genetic screen for novel regulators of circadian rhythms, we found that mice lacking MAGED1 (Melanoma Antigen Family D1) exhibit a shortened period and altered rest-activity bouts. These circadian phenotypes are proposed to be caused by a direct effect on the core molecular clock network that reduces the robustness of the circadian clock. We provide in vitro and in vivo evidence indicating that MAGED1 binds to RORalpha to bring about positive and negative effects on core clock genes of Bmal1, Rev-erbalpha and E4bp4 expression through the Rev-Erbalpha/ROR responsive elements (RORE). Maged1 is a non-rhythmic gene that, by binding RORalpha in non-circadian way, enhances rhythmic input and buffers the circadian system from irrelevant, perturbing stimuli or noise. We have thus identified and defined a novel circadian regulator, Maged1, which is indispensable for the robustness of the circadian clock to better serve the organism.
Insights
Mice lacking MAGED1 (Melanoma Antigen Family D1) show disrupted circadian rhythms. MAGED1 regulates core clock genes by interacting with RORalpha, enhancing circadian robustness and buffering against noise.
Area of Science:
- Chronobiology
- Molecular Biology
- Genetics
Background:
- The circadian clock synchronizes physiology with daily environmental changes.
- Disruptions in circadian rhythms are linked to various health issues.
- Identifying novel regulators is crucial for understanding clock function.
Purpose of the Study:
- To identify novel regulators of circadian rhythms.
- To investigate the role of MAGED1 (Melanoma Antigen Family D1) in circadian clock function.
- To elucidate the molecular mechanisms by which MAGED1 influences core clock gene expression.
Main Methods:
- Genetic screening in mice to identify circadian rhythm regulators.
- In vitro and in vivo experiments to assess MAGED1's molecular interactions.
- Analysis of core clock gene expression (Bmal1, Rev-erbalpha, E4bp4) in MAGED1-deficient mice.
Main Results:
- Mice lacking MAGED1 exhibit a shortened circadian period and altered activity patterns.
- MAGED1 directly binds to RORalpha, modulating the expression of key clock genes.
- MAGED1 acts as a non-rhythmic factor that enhances circadian rhythm robustness.
Conclusions:
- MAGED1 is a novel and essential regulator of the mammalian circadian clock.
- MAGED1's interaction with RORalpha stabilizes the molecular clockwork.
- MAGED1 plays a critical role in buffering the circadian system against environmental perturbations.
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