Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis

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Title: Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis
Author(s): Brown, R
Curry, E
Zeller, C
Masrour, N
Patten, D
Gallon, J
Wilhelm-Benartzi, C
Ghaem-Maghami, S
Bowtell, D
Item Type: Journal Article
Abstract: Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.
Publication Date: 3-May-2018
Date of Acceptance: 10-Jan-2018
URI: http://hdl.handle.net/10044/1/55837
DOI: https://dx.doi.org/10.1158/0008-5472.CAN-17-1650
ISSN: 1538-7445
Publisher: American Association for Cancer Research
Start Page: 1383
End Page: 1391
Journal / Book Title: Cancer Research
Volume: 78
Issue: 6
Copyright Statement: ©2018 American Association for Cancer Research.
Sponsor/Funder: Ovarian Cancer Action
Funder's Grant Number: N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
STEM-CELLS
CANCER
METHYLATION
POLYCOMB
EPIGENOME
PATTERN
MODULE
MOUSE
EZH2
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Embargo Date: 2019-01-16
Online Publication Date: 2018-01-16
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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