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    EPIGENETICS TUNE CHROMATIN MECHANICS, A COMPUTATIONAL APPROACH

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    Date
    2021
    Author
    Pitman, Mary
    Advisor
    Papoian, Garegin A
    DRUM DOI
    https://doi.org/10.13016/ibu6-xfgb
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    Abstract
    The base unit of DNA packaging in eukaryotes, the nucleosome, is adaptively modified for epigenetic control. Given the vast chemical space of chromatin and complexity of signaling and expression, much of our knowledge about genetic regulation comes from a biochemical or structural perspective. However, the architecture and function of chromatin also mechanically responds to non-equilibrium forces. Mechanical and biochemical properties are not independent of one another and the interplay of both of these material properties is an area of chromatin physics with many remaining questions. Therefore, I set out to determine how the material properties of chromatin are altered by biochemical variations of nucleosomes. All-atom molecular dynamics is employed coupled with new computational and theoretical tools. My findings and predictions were collaboratively validated and biologically contextualized through multiscale experimental methods. First, I computationally discover that epigenetic switches buried within the nucleosome core alter DNA accessibility and the recruitment of essential proteins for mitosis. Next, using new computational tools, I report that centromeric nucleosomes are more elastic than their canonical counterparts and that centromeric nucleosomes rigidify when seeded for kinetochore formation. We conclude that the material properties of variants and binding events correlate with modified loading of transcriptional machinery. Further, I present my theoretical approach called Minimal Cylinder Analysis (MCA) that uses strain fluctuations to determine the Young's modulus of nucleosomes from all-atom molecular dynamics simulations. I show and explain why MCA achieves quantitative agreement with experimental measurements. Finally, the elasticity of hybrid nucleosomes in cancer is measured from simulation, and I implicate this oncogenic variant in potential neocentromere formation. Together, these data link the physics of nucleosome variations to chromatin states' plasticity and biological ramifications.
    URI
    http://hdl.handle.net/1903/27811
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    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
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