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Determinants of histone H1 dynamics in vivo

  • Author / Creator
    Raghuram, Nikhil
  • Chromatin plays a pivotal role in regulating critical DNA dependent processes, such as transcription. Chromatin and associated epigenetic modifications form the molecular basis of differentiation and development and are misregulated in disease states, such as cancer. Histone H1 molecules are key players in epigenetic mechanisms and are involved in the formation and stabilization of higher order chromatin structures, as well as having gene specific effects in transcription. Post-translational modifications, such as core histone acetylation and H1 phosphorylation, modify H1 binding and thus alter H1 function, although the underlying molecular mechanisms are unknown. We have used live cell imaging techniques, such as FRAP, to elucidate the complex binding events of H1 in response to chromatin modifying events during transcription. Using this approach, we have described the changes in H1 dynamics upon induction of core histone acetylation and how cooperativity of H1 binding is changed upon this modification. Using classical biochemical experiments and imaging techniques, we have shown a novel interaction between phosphorylated H1 molecules and a nuclear prolyl-isomerase, Pin1. This establishes phosphorylation-dependent proline isomerization of H1 as a key regulatory event during transcriptional initiation. Pin1 and core histone acetylation impart changes in one or more of the binding steps of H1, impeding H1 function. This can have consequences on the stability of higher orders of chromatin structure. Our studies provide mechanistic insight towards the epigenetic regulation of H1 and chromatin structure in transcriptional processes.

  • Subjects / Keywords
  • Graduation date
    2013-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R32P71
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Oncology
  • Specialization
    • Experimental Oncology
  • Supervisor / co-supervisor and their department(s)
    • Dr. Michael J Hendzel (Department of Oncology)
  • Examining committee members and their departments
    • Dr. Gordon Chan (Department of Oncology)
    • Dr. Luis Schang (Department of Biochemistry)
    • Dr. John Lewis (Department of Oncology)
    • Dr. Chris Nelson (Department of Biochemistry and Microbiology)