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MULTIPLE FUNCTIONS OF THE PR-SET7 HISTONE METHYLTRANSFERASE:
FROM TRANSCRIPTION TO THE CELL CYCLE
by
Lauren Marie Congdon
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2012
Copyright 2012 Lauren Marie Congdon
Object Description
| Title | Multiple functions of the PR-Set7 histone methyltransferase: from transcription to the cell cycle |
| Author | Congdon, Lauren Marie |
| Author email | lcongdon@usc.edu;lauren.congdon@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular and Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2012-09-28 |
| Date submitted | 2012-11-14 |
| Date approved | 2012-11-15 |
| Restricted until | 2012-11-15 |
| Date published | 2012-11-15 |
| Advisor (committee chair) | Rice, Judd C. |
| Advisor (committee member) |
Goldkorn, Amir An, Woojin Hsieh, Chih-Lin |
| Abstract | Within the eukaryotic nucleus, DNA is packaged via its interaction with histones and non-histone proteins into a structure known as chromatin. Chromatin is dynamic in nature, and can become more condensed or more accessible depending on, among other things, the post-translational modifications present on the histone proteins. Histone-modifying enzymes can alter the configuration of chromatin and are known to play essential roles in DNA-templated processes, including gene transcription, cell cycle progression and DNA damage repair pathways. This dissertation presents novel findings on the functions and binding partners of the PR-Set7 histone H4 lysine 20 monomethyltransferase. ❧ Several lines of evidence have been reported implicating PR-Set7 in both transcriptional repression and activation. Chapter 1 presents our efforts to more clearly elucidate the role of PR-Set7 and H4K20me1 in transcription. In short, we found that depletion of PR-Set7 or its catalytic activity resulted in the de-repression of newly identified PR-Set7 target genes, strongly suggesting that PR-Set7 and H4K20me1 function in the transcriptional repression of specific genes. ❧ A ‘histone code’ hypothesis has been proposed, in which specific combinations of post-translational modifications on histone tails may function coordinately to regulate distinct chromatin-templated processes. We previously reported a novel trans-tail histone code involving monomethylated H4K20 and H3K9. We found that global H3K9 monomethylation requires PR-Set7 but does not require its catalytic activity. We therefore predicted that PR-Set7 recruits an unidentified H3K9 methyltransferase to establish this novel histone code. In Chapter 2 we identify this H3K9 methyltransferase as Riz1 (PRDM2/KMT8). Riz1 is a tumor suppressor, and is frequently mutated in human cancers by a frameshift mutation resulting in the expression of a truncated protein lacking the C-terminal domain found to be required for PR-Set7 binding and proper localization. Finally, forced ectopic expression of wild type Riz1 in cancer cell lines carrying this Riz1 truncation mutation resulted in cell cycle arrest and apoptosis. These data indicate that Riz1 is an important tumor suppressor and imply that direct Riz1 binding to PR-Set7 is required for proper Riz1 localization and function. ❧ In Chapter 3 we demonstrate that PR-Set7 interacts with class I HDAC proteins in vivo, and that treatment with class I HDAC inhibitors results in the selective de-repression of PR-Set7 target genes. Furthermore, we found that PR-Set7 directly binds HDAC3 in vitro and that this interaction may be functionally significant in epithelial-mesenchymal transition. Together, these results suggest that PR-Set7 and class I HDACs cooperate to regulate transcription of specific human genes. ❧ Lastly, in Chapter 4 we present evidence that after osmotic stress, PR-Set7 is phosphorylated at serine 29 by JNK kinase, and that this modification protects PR-Set7 from degradation after UV irriadiation. Collectively, this dissertation presents novel findings regarding PR-Set7’s binding to other histone-modifying enzymes, Riz1 and HDAC3. These findings help to improve our understanding of PR-Set7 function during transcriptional repression and cell cycle progression, as well as provide insights into how perturbation of PR-Set7 may contribute to cancer development and progression. |
| Keyword | histone code; histone methylation; PR-Set7; Riz1; transcription |
| 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 |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Congdon, Lauren Marie |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-CongdonLau-1293.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | MULTIPLE FUNCTIONS OF THE PR-SET7 HISTONE METHYLTRANSFERASE: FROM TRANSCRIPTION TO THE CELL CYCLE by Lauren Marie Congdon A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR AND CELLULAR BIOLOGY) December 2012 Copyright 2012 Lauren Marie Congdon |
