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RUNX2 INTERACTIONS WITH THE OSTEOBLAST GENOME
by
Steven Pregizer
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 & MOLECULAR BIOLOGY)
August 2008
Copyright 2008 Steven Pregizer
Object Description
| Title | Runx2 interactions with the osteoblast genome |
| Author | Pregizer, Steven |
| Author email | pregizer@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-13 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-07-15 |
| Advisor (committee chair) | Frenkel, Baruch |
| Advisor (committee member) |
Hacia, Joseph Rice, Judd Coetzee, Gerhard |
| Abstract | Runx2 is a master transcription factor in osteoblasts, yet its mechanism is poorly understood. In particular, there is a paucity of information about its target genes and their regulation. To address this, we first used ChIP Display to discover novel genomic targets occupied by Runx2 in living MC3T3-E1 osteoblastic cells. One of these targets was located within the promoter of Tram2, whose product facilitates proper folding of type I collagen. We demonstrated that Tram2 mRNA levels were altered by exogenous Runx2, and that this occurred in a BMP- and cell typedependent manner. Thus, Tram2 is likely a Runx2 target gene and may participate in its osteogenic function. Next, we measured endogenous Runx2 expression in MC3T3-E1 cells during development of the osteoblast phenotype, to see if it could explain the dramatic increase in mRNA levels of Osteocalcin (OC), a classic Runx2 target gene. Surprisingly, we discovered that it could not, as Runx2 expression decreased over time, along with in vitro DNA binding activity. Instead, developmental stimulation of OC by Runx2 is attributable to enhanced promoter occupancy in vivo. A remarkably similar pattern of recruitment was observed at the Glt28d2 promoter, a novel Runx2 genomic target discovered by ChIP-Chip analysis of cells in which the OC promoter is maximally occupied. Thus, Runx2 acquires the ability to access target genes relatively late during development of the osteoblast phenotype, and this is most likely due to activation of collaborating factors or to post-translational modification of Runx2 itself. Expanding our knowledge of Runx2 target genes and their regulation is warranted to better understand the regulation of osteoblast function and to provide opportunities for the development of new bone anabolics. |
| Keyword | Runx2; osteoblast differentiation; transcriptional regulation; location analysis |
| 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-m1349 |
| Rights | Pregizer, Steven |
| 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-Pregizer-20080715 |
| Archival file | uscthesesreloadpub_Volume44/etd-Pregizer-20080715.pdf |
Description
| Title | Page 1 |
| Full text | RUNX2 INTERACTIONS WITH THE OSTEOBLAST GENOME by Steven Pregizer 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 & MOLECULAR BIOLOGY) August 2008 Copyright 2008 Steven Pregizer |
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