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

Curry, Edward, Zeller, Constanze, Masrour, Nahal, Patten, Darren K., Gallon, John, Wilhelm-Benartzi, Charlotte S., Ghaem-Maghami, Sadaf, Bowtell, David D. and Brown, Robert 2018. Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis. Cancer Research 78 (6) , pp. 1383-1391. 10.1158/0008-5472.CAN-17-1650

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Centre for Trials Research (CNTRR)
Medicine
Publisher: American Association for Cancer Research
ISSN: 0008-5472
Date of First Compliant Deposit: 12 November 2019
Date of Acceptance: 10 January 2018
Last Modified: 12 Nov 2019 10:29
URI: http://orca.cf.ac.uk/id/eprint/124772

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