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    Polycomb PRC2-Ezh1 cell memory system in circadian clock and diet induced cellular stress regulation in mammalian skeletal muscle

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    Name:
    Seba Nadeef Dissertation.pdf
    Size:
    5.851Mb
    Format:
    PDF
    Description:
    PhD Dissertation
    Embargo End Date:
    2021-12-02
    Download
    Type
    Dissertation
    Authors
    Nadeef, Seba S. cc
    Advisors
    Orlando, Valerio cc
    Committee members
    Sassone-Corsi, Paolo
    Croce, Luciano Di
    Habuchi, Satoshi cc
    Blilou, Ikram cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2019-11
    Embargo End Date
    2021-12-02
    Permanent link to this record
    http://hdl.handle.net/10754/660378
    
    Metadata
    Show full item record
    Access Restrictions
    At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation will become available to the public after the expiration of the embargo on 2021-12-02.
    Abstract
    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 including chronic metabolic disorders, muscle waste and cardiopathies. Previous studies 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. We hypothesized that Ezh1 could play an important role in circadian clock regulation in post-mitotic skeletal muscle, 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), localized specifically in the cytoplasm and controlling stress induced nuclear PRC2 activity, was completely disrupted under HFD. More interestingly, the circadian pattern of core clock components was impaired in Ezh1 depleted cells. Our data unveils an interesting physiological role of the 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.
    Citation
    Nadeef, S. S. (2019). Polycomb PRC2-Ezh1 cell memory system in circadian clock and diet induced cellular stress regulation in mammalian skeletal muscle. KAUST Research Repository. https://doi.org/10.25781/KAUST-85885
    DOI
    10.25781/KAUST-85885
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-85885
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Dissertations

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