PhD Advisor: Valerio Orlando
The majority of our physiological and metabolic processes are coordinated by an internal clock, which has evolved as an adaptive response to the daily light-dark cycles. Thus, several physiological and behavioral activities display an oscillatory rhythmic period of 24 hours. This highly conserved molecular mechanism is achieved through a specific program of gene expression, characterized by a complex interaction between clock-core proteins, chromatin remodelers and epigenetic events associated with the oscillatory nature of circadian transcriptional activity in the genome. Clock disruption leads to a wide spectrum of severe health problems associated including chronic metabolic disorders, muscle waste and cardiopathies. Recent evidence revealed that each cell and organ possess an intrinsic clock and that coordination between central versus peripheral clocks is key for health. Furthermore, it has been found that under nutritional challenge such as High Fat Diet (HFD), the circadian transcriptome and metabolome are rapidly remodeled in the mouse model. Surprisingly, metabolome and gene expression analysis on various tissues revealed that skeletal muscle is the most affected under HFD.Mechanisms that regulate circadian cycle and stress induced rapid adaptation and in particular metabolic stress at the chromatin level are largely unknown. In this study, we investigated the role of Polycomb proteins group (PcG) mediate cell memory system by maintaining transcriptional gene silencing, in particular the PRC2-EZH1 complex and its role in adaptive transcriptional gene silencing in post-mitotic skeletal muscle, circadian clock regulation and metabolic stress. We hypothesized that Ezh1 could play an important role in circadian clock regulation, and this pathway has never been explored in this context. We explored the circadian role of PRC2-Ezh1 in the mouse skeletal muscle. Intriguingly, we found that the oscillatory profile, of a novel isoform of Ezh1 (Ezh1beta) specifically present in the cytoplasm and controlling stress induced nuclear PRC2 activity, was completely disrupted under HFD. More interestingly, circadian pattern of core clock component was impaired in Ezh1 depleted cells. Our data unveils an interesting physiological role of PcG memory system, from cytoplasm to chromatin, which could indicate a new link between the chromatin remodeler Polycomb proteins and the endogenous clock in adaptation mechanism in skeletal muscle. The results of this project along with our future hypothesis, will provide a comprehensive picture of the contribution of epigenetics in numerous chronic diseases and will shed light on novel fundamental mechanistic aspects underlying circadian clock regulation, possibly relevant for associated high societal impact diseases.
Seba Nadeef was born in Taif, Saudi Arabia. She received her Bachelor of Biotechnology from Taif University and Masters degree in Bioscience from King Abdullah University of Science & Technology (KAUST). She is now a PhD candidate in Bioscience at KAUST under the supervision of Prof. Valerio Orlando with colaboration with University of California, Irvine (UCI).