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STUDIES OF THE BIOLOGICAL RELEVANCE OF HISTONE H4 LYSINE
20 MONOMETHYLATION: DISCOVERY OF ITS ROLE IN THE CELL
CYCLE AND LOCALIZATION WITHIN THE HUMAN GENOME
by
Sabrina Ishimaru Houston
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2007
Copyright 2007 Sabrina Ishimaru Houston
Object Description
| Title | Studies of the biological relevance of Histone H4 Lysine 20 monomethylation: discovery of its role in the cell cycle and localization within the human genome |
| Author | Houston, Sabrina Ishimaru |
| Author email | shouston@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2007-07-20 |
| Date submitted | 2007 |
| Restricted until | Restricted until 19 Sept. 2009. |
| Date published | 2009-09-19 |
| Advisor (committee chair) | Rice, Judd |
| Advisor (committee member) |
[illegible], Ite A. Frenkel, Baruch Jadner, Robert D. |
| Abstract | The post-translational modification of histones is thought to play a critical role in directing nuclear events involving chromatin. One such modification, Histone H4 Lysine 20 (H4K20) methylation, a mark only seen in multicellular eukaryotes, has been shown to be associated with inactive chromatin. Here, we performed chromatin immunoprecipitation experiments on genomic tiled arrays of human chromosomes 21 and 22 to discover the genomic localization of H4K20 monomethylation. A novel statistical method was used to cull genomic regions enriched for H4K20 monomethylation. It was found that H4K20 monomethylation often occurs within genes, at minisatellite repeats, and at sites of high conservation within higher eukaryotes. H4K20 monomethylation was confirmed as being a transcriptionally repressive mark by analyzing the expression analysis of highly H4K20 monomethylated genes in the presence and absence of this modification. Sequences with a high degree of H4K20 monomethylation were found to have a negative effect on transcription, due to a higher propensity for chromatinization. H4K20 monomethylation was also found to have a cell cycle regulated profile, peaking at G2/M, while being absent at the G1/S border. PR-Set7, a cell cycle regulated histone methyltransferase, has been shown to be responsible for the bulk of H4K20 mono-methylation. We found that knockdown of PR-Set7 and H4K20 mono-methylation leads to severe growth arrest. Growth arrest was found to be accompanied by the appearance of DNA damage, as measured by increased levels of H2AX phosphorylation and comet assay. Multiple mitotic spindles, another hallmark of DNA damage, were observed in cells lacking H4K20 monomethylation. These cells were also found to have high levels of enlarged nuclei, whose chromatin appeared less densely packed than corresponding normal sized nuclei. A global decrease in chromatin condensation upon PR-Set7 knockdown was confirmed with micrococcal nuclease assays.; Together, these studies indicate that while H4K20 monomethylation plays a role in transcriptional repression, it also plays a major role in cell cycle progression, chromatin condensation and protection from DNA damage. |
| Keyword | epigenetics; histone methylation |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m828 |
| Rights | Houston, Sabrina Ishimaru |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Houston-20070919 |
| Archival file | uscthesesreloadpub_Volume14/etd-Houston-20070919.pdf |
Description
| Title | Page 1 |
| Full text | STUDIES OF THE BIOLOGICAL RELEVANCE OF HISTONE H4 LYSINE 20 MONOMETHYLATION: DISCOVERY OF ITS ROLE IN THE CELL CYCLE AND LOCALIZATION WITHIN THE HUMAN GENOME by Sabrina Ishimaru Houston A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2007 Copyright 2007 Sabrina Ishimaru Houston |
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