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DNA methylation and histone modifica...

McGarvey, Kelly Marie.

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DNA methylation and histone modifications: Connections in a cancer setting.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	DNA methylation and histone modifications: Connections in a cancer setting./
Author:	McGarvey, Kelly Marie.
Description:	121 p.
Notes:	Adviser: Stephen B. Baylin.
Contained By:	Dissertation Abstracts International68-11B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3288503
ISBN:	9780549312147

DNA methylation and histone modifications: Connections in a cancer setting.
McGarvey, Kelly Marie.

DNA methylation and histone modifications: Connections in a cancer setting. - 121 p.

Adviser: Stephen B. Baylin.

Thesis (Ph.D.)--The Johns Hopkins University, 2008.

DNA methylation and chromatin modifications are two important features associated with epigenetic gene regulation. While epigenetic regulation is important for normal cellular processes, dysregulation of the epigenetic machinery appears to be a key factor in the initiation and progression of cancer. Using DNA hypermethylated and silenced tumor suppressor genes as a model system, we attempted to better understand the relationship and interdependence between DNA methylation and histone modifications.

ISBN: 9780549312147Subjects--Topical Terms:

1017719
Biology, Molecular.

DNA methylation and histone modifications: Connections in a cancer setting.
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020 $a 9780549312147
035 $a (UMI)AAI3288503
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100 1 $a McGarvey, Kelly Marie. $3 1269372
245 1 0 $a DNA methylation and histone modifications: Connections in a cancer setting.
300 $a 121 p.
500 $a Adviser: Stephen B. Baylin.
500 $a Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7121.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2008.
520 $a DNA methylation and chromatin modifications are two important features associated with epigenetic gene regulation. While epigenetic regulation is important for normal cellular processes, dysregulation of the epigenetic machinery appears to be a key factor in the initiation and progression of cancer. Using DNA hypermethylated and silenced tumor suppressor genes as a model system, we attempted to better understand the relationship and interdependence between DNA methylation and histone modifications.
520 $a We first sought to determine what effect loss of DNA methylation in cancer cell lines has on histone modifications at re-expressed genes. We first used chromatin immunoprecipitation (ChIP) to compare the hMLH1 gene promoter when it is basally expressed in SW480 cells versus in RKO cells where the promoter is DNA hypermethylated and silenced. We demonstrated that all forms of repressive histone modifications examined, including mono-, di-, and trimethylation of H3K9 and H3K27, were enriched at a silent promoter versus an active one. Histone modification changes at several tumor suppressor gene promoters were then tracked after depletion of DNA methylation, either by the agent 5-aza-2'-deoxycytidine (5-aza-dC), or by genetic knockout of DNMT1 and DNMT3b in the colorectal cancer cell line HCT116. Strikingly, H3K9me1 and H3K9me2 were the only histone marks depleted after DNA demethylation and gene reactivation. Some of the "repressive" marks, including H3K9me3 and H3K27me3, actually increased at many of the examined promoters. We suggest that these re-expressed tumor suppressor genes do not return to a fully euchromatic chromatin state, but instead are held in a semi-heterochromatic state where these genes are poised for re-silencing. Future studies in this system on a more global scale will help to elucidate the important chromatin changes occurring after DNA demethylation.
520 $a With knowledge of the histone methyltransferases and histone marks that are present at silent tumor suppressor genes, we then set out to determine the effect that a key histone methyltransferase (and associated histone mark) has on DNA methylation and gene silencing. There is some evidence that histone modifications may be necessary for initiation and maintenance of DNA methylation, but little is known in the setting of silenced genes with densely hypermethylated CpG islands. In order to better understand this interplay in mammalian cells, we used siRNA to knockdown the histone 3 lysine 27 (H3K27) methyltransferase, EZH2. We found that while we were able to reduce global levels of H3K27 trimethylation (H3K27me3), as well as local levels at hypermethylated CpG islands, we did not see concurrent gene re-expression or loss of DNA methylation. Alternately, we witnessed an increase in expression of genes that were basally expressed and that did not show an appreciable amount of promoter hypermethylation. This suggests that while EZH2 is important for modulating expression levels of basally expressed genes, it is not necessary for maintenance of DNA methylation at silenced tumor suppressor gene promoters.
590 $a School code: 0098.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
690 $a 0307
690 $a 0992
710 2 $a The Johns Hopkins University. $3 1017431
773 0 $t Dissertation Abstracts International $g 68-11B.
790 $a 0098
790 1 0 $a Baylin, Stephen B., $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3288503