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THE ROLE OF HISTONE H4 LYSINE 20 MONOMETHYLATION IN REGULATING
GENE EXPRESSION AND DIFFERENTIATION
by
Jennifer Kae Sims
__________________________________________________________________
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)
August 2008
Copyright 2008 Jennifer Kae Sims
Object Description
| Title | The role of histone H4 lysine 20 monomethylation in gene expression and differentiation |
| Author | Sims, Jennifer Kae |
| Author email | stemple@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-04-21 |
| Date submitted | 2008 |
| Restricted until | Restricted until 14 July 2010. |
| Date published | 2010-07-14 |
| Advisor (committee chair) | Rice, Judd |
| Advisor (committee member) |
An, Woojin Laird, Peter Aparicio, Oscar |
| Abstract | In developing multi-cellular organisms, cell fate decisions are largely determined by epigenetic programs that activate and repress specific sets of genes. For eukaryotic gene regulation, the post-translational modifications of the DNA-associated histone proteins are critical in transcriptional control. Here, we describe a novel trans-tail histone code where the monomethylation of histones H4 lysine 20 (H4K20) and H3 lysine 9 (H3K9) defines specific genomic regions of transcriptionally repressed chromatin. Global analysis of this code revealed a defined unidirectional temporal sequence of methylmodifications in which monomethylated H3K9 depends on the H4K20 monomethyltransferase, PR-Set7. Importantly, we have identified a repressor protein, L3MBTL1, which is recruited to and binds monomethylated H4K20 and that this interaction is required to initiate transcriptional repression in vivo. Using expression microarray analysis, we have identified numerous cell type-specific genes involved in certain growth and differentiation pathways whose expression is directly regulated by the H4K20 monomethylation silencing pathway.; By focusing on one of these genes, RUNX1/AML1, we found that monomethylation of H4K20 by PR-Set7 was required for chromatin condensation and transcriptional repression but that H3K9 monomethylation was dispensable. We also confirmed that the H4K20 monomethyl-binding protein, L3MBTL1, was required but not sufficient for RUNX1 repression. Importantly, we demonstrated that the lack of monomethylated H4K20 at the RUNX1 promoter results in increased RUNX1 protein expression and the spontaneous differentiation of BFU-E/MK precursor cells specifically to the megakaryocytic lineage. We have further extended these studies to examine the role of histone methylation patterns during embryonic stem cell commitment. Using both Western analysis as well as high throughput microarray analysis, we demonstrate clear changes in histone methylation patterns as stem cells move from pluripotency to commitment phase. Collectively, these studies demonstrate that histone methylation plays a critical role in human development. |
| Keyword | histone H4 lysine 20; gene expression; differentiation |
| 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-m1343 |
| Rights | Sims, Jennifer Kae |
| 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-Sims-20080714 |
| Archival file | uscthesesreloadpub_Volume40/etd-Sims-20080714.pdf |
Description
| Title | Page 1 |
| Full text | THE ROLE OF HISTONE H4 LYSINE 20 MONOMETHYLATION IN REGULATING GENE EXPRESSION AND DIFFERENTIATION by Jennifer Kae Sims __________________________________________________________________ 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) August 2008 Copyright 2008 Jennifer Kae Sims |
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