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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Date
2018-03-15ICR Author
Author
Curry, E
Zeller, C
Masrour, N
Patten, DK
Gallon, J
Wilhelm-Benartzi, CS
Ghaem-Maghami, S
Bowtell, DD
Brown, R
Type
Journal Article
Metadata
Show full item recordAbstract
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.Significance: These results suggest epigenetic targets for intervention to prevent the emergence of cancer drug resistance. Cancer Res; 78(6); 1383-91. ©2018 AACR.
Collections
Subject
Chromatin
Humans
Ovarian Neoplasms
Histones
Chromatin Immunoprecipitation
DNA Methylation
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Silencing
Histone Code
CpG Islands
Drug Resistance, Neoplasm
Female
Promoter Regions, Genetic
Carcinoma, Ovarian Epithelial
Research team
Medicine (Brown Epigenetic Therapy)
Language
eng
Date accepted
2018-01-10
License start date
2018-03
Citation
Cancer research, 2018, 78 (6), pp. 1383 - 1391
Publisher
AMER ASSOC CANCER RESEARCH