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Coordinate study of DNA methylation ...

Pandiyan, Kurinji.

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Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations./
Author:	Pandiyan, Kurinji.
Description:	181 p.
Notes:	Source: Dissertation Abstracts International, Volume: 75-06(E), Section: B.
Contained By:	Dissertation Abstracts International75-06B(E).
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3579527
ISBN:	9781303769290

Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations.
Pandiyan, Kurinji.

Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations. - 181 p.

Source: Dissertation Abstracts International, Volume: 75-06(E), Section: B.

Thesis (Ph.D.)--The Johns Hopkins University, 2013.

This item is not available from ProQuest Dissertations & Theses.

DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (AZA, 5-Aza-CdR) are currently used for the treatment of myelodysplastic syndrome. Although global DNA demethylation has been observed after treatment, it is unclear to what extent demethylation induces changes in nucleosome occupancy, a key determinant of gene expression. We use the colorectal cancer cell line HCT116 as a model to address this question and determine that <2% of regions demethylated by 5-Aza-CdR treatment assume an open configuration. Consolidating our findings, we detect nucleosome retention at sites of global DNA methylation loss in DKO1, an HCT116-derived non-tumorigenic cell-line engineered for DNA methyltransferase disruption. Notably, regions that are open in both HCT116 cells after treatment and in DKO1 cells include promoters belonging to tumor suppressors and genes under-expressed in colorectal cancers. Our results indicate that only a minority of demethylated promoters is associated with nucleosome remodeling, and these could potentially be the epigenetic drivers causing the loss of tumorigenicity. Furthermore, we show that the chromatin opening induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid has strikingly distinct targets compared with those of 5-Aza-CdR, providing a mechanistic explanation for the importance of combinatorial therapy in eliciting maximal de-repression of the cancer epigenome.

ISBN: 9781303769290Subjects--Topical Terms:

3172791
Cellular biology.

Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations.
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100 1 $a Pandiyan, Kurinji. $3 3174665
245 1 0 $a Coordinate study of DNA methylation and chromatin accessibility reveals functional epigenetic alterations.
300 $a 181 p.
500 $a Source: Dissertation Abstracts International, Volume: 75-06(E), Section: B.
500 $a Adviser: Stephen B. Baylin.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2013.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a DNA methylation inhibitors such as 5-aza-2'-deoxycytidine (AZA, 5-Aza-CdR) are currently used for the treatment of myelodysplastic syndrome. Although global DNA demethylation has been observed after treatment, it is unclear to what extent demethylation induces changes in nucleosome occupancy, a key determinant of gene expression. We use the colorectal cancer cell line HCT116 as a model to address this question and determine that <2% of regions demethylated by 5-Aza-CdR treatment assume an open configuration. Consolidating our findings, we detect nucleosome retention at sites of global DNA methylation loss in DKO1, an HCT116-derived non-tumorigenic cell-line engineered for DNA methyltransferase disruption. Notably, regions that are open in both HCT116 cells after treatment and in DKO1 cells include promoters belonging to tumor suppressors and genes under-expressed in colorectal cancers. Our results indicate that only a minority of demethylated promoters is associated with nucleosome remodeling, and these could potentially be the epigenetic drivers causing the loss of tumorigenicity. Furthermore, we show that the chromatin opening induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid has strikingly distinct targets compared with those of 5-Aza-CdR, providing a mechanistic explanation for the importance of combinatorial therapy in eliciting maximal de-repression of the cancer epigenome.
520 $a The need for personalized medicine is shaping the development of therapeutic interventions in cancer. Just as mutation spectrums in patients are unique, so are the epigenetic aberrations. Given that it is critical to understand both the DNA methylation aberrations and the changes to the chromatin landscape in a coordinate and inexpensive manner, we extend the global study of chromatin states using our method, AcceSssIble, to uncultured renal clear cell carcinoma (RCC) compared to their matched normal tissues.
520 $a The strength of AcceSssIble lies in the simple and innovative approach to understand the complex regulatory mechanisms of the epigenome in an integrated manner, and the ease of its implementation and data analysis. We demonstrate that the method can be applied to both fresh and archival, frozen primary tissues, and that nucleosome positioning is largely unaltered by the freeze-thaw process. We carefully characterize the spectrum of epigenetic defects in chromatin accessibility that occur dependent on and independent of DNA methylation in three RCC samples compared to their matched normal tissue and identify six distinct groups of epigenetic aberrations, including hyper- and hypo-methylation, as well as gain and loss of accessibility in the tumor. We also identify a panel of candidate common epigenetic driver genes in RCC, under the hypothesis that changes in nucleosome occupancy, with or without changes in DNA methylation, are critical for RCC tumorigenesis. Together, our results demonstrate that it is possible to identify epigenetic driver events using metrics of DNA methylation and chromatin accessibility in patient samples, and paves the way for personalization of epigenetic therapy.
520 $a Although some of the molecular events that mediate the epithelial to mesenchymal transition (EMT), a crucial process in development and in tumorigenesis, have been well established, the study of the epigenomics of this process is still in its infancy. We perform AcceSssIble to coordinately assay DNA methylation and chromatin accessibility changes in TGF-beta and TWIST induced systems of EMT in a human mammary epithelial cell line. We find no DNA methylation changes in the TGF-beta induced EMT system but, in stark contrast, identify that the TWIST system results in DNA demethylation and gain of methylation at several loci. Regions of loss of methylation are enriched for metastasis-related genes, providing biological justification for the demethylation at these loci. Hypothesizing that driver epigenetic changes in EMT were those that involved a chromatin accessibility change, we analyze TWIST-EMT and knock down the mRNA of putative drivers. Of interest, we find that the knock down of two out of the three genes was sufficient to trigger the transition. In this study, we coordinately study DNA methylation and chromatin accessibility changes in two model systems of EMT and use this to identify two novel players that are sufficient to drive this process -- CST6 and TRIM29..
520 $a We believe that our novel method, AcceSssIble, will be of great interest to clinicians and basic scientists alike since it provides a snapshot view of genome-wide chromatin states in a cost-effective, rapid manner. It can be applied to the study of DNA methylation and the dynamics of chromatin accessibility in diverse cellular and tissue samples, for the understanding of changes during development, tumorigenesis and to monitor and develop new epigenetic therapies.
590 $a School code: 0098.
650 4 $a Cellular biology. $3 3172791
650 4 $a Genetics. $3 530508
650 4 $a Oncology. $3 751006
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710 2 $a The Johns Hopkins University. $3 1017431
773 0 $t Dissertation Abstracts International $g 75-06B(E).
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791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3579527