Page 1 |
Save page Remove page | Previous | 1 of 191 | Next |
|
small (250x250 max)
medium (500x500 max)
large ( > 500x500)
Full Resolution
All (PDF)
|
This page
All
Subset |
ROLE OF DNA METHYLTRANSFERASES 3A AND 3B IN
INHERITANCE OF DNA METHYLATION PATTERNS
by
Shikhar Sharma
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 2010
Copyright 2010 Shikhar Sharma
Object Description
| Title | Role of DNA methyltransferases 3A and 3B in inheritance of DNA methylation patterns |
| Author | Sharma, Shikhar |
| Author email | shikhars@usc.edu; shikharsharma@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular & Cellular Biology |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-11-18 |
| Advisor (committee chair) | Jones, Peter A. |
| Advisor (committee member) |
Coetzee, Gerhard A. Stallcup, Michael R. |
| Abstract | Proper propagation of epigenetic information during somatic cell divisions is critical for preserving gene expression patterns and cellular identity. However, the molecular mechanisms responsible for faithful inheritance of epigenetic marks are still poorly understood. In this thesis work, I have studied the inheritance of DNA methylation patterns through somatic divisions, focusing on the role of DNA methyltransferases 3A and 3B in this process.; DNA methylation patterns are established during development and then maintained through multiple somatic cell divisions by co-operative activity of the de novo and maintenance DNA methyltransferases - DNMT3A/3B and DNMT1, respectively. A key question that remains unresolved is how the de novo DNMT3A/3B enzymes assist in faithful inheritance of methylation patterns in somatic cells while guarding against aberrant de novo DNA methylation. Using sucrose density gradient analyses of fractionated chromatin, I have shown that almost all of the cellular contents of DNMT3A/3B, but not DNMT1, are strongly anchored to nucleosomes containing methylated DNA, allowing little free DNMT3A/3B to exist in the nucleus. This binding of DNMT3A/3B to nucleosomes does not require the presence of other known chromatin-associated proteins such as PCNA, HP1, MeCP2, EZH2, HDAC1, UHRF1 and G9a, but does require synergistic interactions of the conserved domains of DNMT3A/3B with the intact nucleosomes. The PWWP domain of DNMT3A assists such nucleosome binding through interaction with the H3K36me3 mark. Further, tight binding of DNMT3A/3B to nucleosomes in the presence of DNA methylation stabilizes these proteins. Drastic reduction of cellular DNA methylation levels results in a dramatic transcription-independent decrease of DNMT3A/3B proteins due to reduced nucleosome binding and subsequent degradation of the unstable free protein. Stabilization of DNMT3A/3B on nucleosomes in methylated regions promotes propagation of DNA methylation with DNMT3A/3B working synergistically in this maintenance process. Taken together, this thesis work presents an unexpected self-regulatory inheritance mechanism which not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes. |
| Keyword | DNA methylation; nucleosome; DNMT3A; DNMT3B; epigenetics; inheritance |
| 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-m3538 |
| Rights | Sharma, Shikhar |
| 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-Sharma-4153 |
| Archival file | uscthesesreloadpub_Volume32/etd-Sharma-4153.pdf |
Description
| Title | Page 1 |
| Full text | ROLE OF DNA METHYLTRANSFERASES 3A AND 3B IN INHERITANCE OF DNA METHYLATION PATTERNS by Shikhar Sharma 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 2010 Copyright 2010 Shikhar Sharma |
Comments
Post a Comment for Page 1
