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Permanent link (DOI): https://doi.org/10.7939/R32P71

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Determinants of histone H1 dynamics in vivo Open Access

Descriptions

Other title
Subject/Keyword
Histone H1
Proline isomerization
Chromatin
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Raghuram, Nikhil
Supervisor and department
Dr. Michael J Hendzel (Department of Oncology)
Examining committee member and department
Dr. Chris Nelson (Department of Biochemistry and Microbiology)
Dr. Gordon Chan (Department of Oncology)
Dr. John Lewis (Department of Oncology)
Dr. Luis Schang (Department of Biochemistry)
Department
Department of Oncology
Specialization
Experimental Oncology
Date accepted
2013-01-07T14:23:56Z
Graduation date
2013-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R32P71
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Core histone hyperacetylation impacts cooperative behavior and high-affinity binding of histone H1 to chromatin. Raghuram N, Carrero G, Stasevich TJ, McNally JG, Th'ng J, Hendzel MJ. Biochemistry. 2010 Jun 1;49(21):4420-31.

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File author: Nikhil Raghuram
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