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dc.contributor.authorCurry, E
dc.contributor.authorZeller, C
dc.contributor.authorMasrour, N
dc.contributor.authorPatten, DK
dc.contributor.authorGallon, J
dc.contributor.authorWilhelm-Benartzi, CS
dc.contributor.authorGhaem-Maghami, S
dc.contributor.authorBowtell, DD
dc.contributor.authorBrown, R
dc.date.accessioned2019-02-25T11:46:36Z
dc.date.issued2018-03
dc.identifier.citationCancer research, 2018, 78 (6), pp. 1383 - 1391
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3082
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-17-1650
dc.description.abstractBivalent 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.
dc.formatPrint-Electronic
dc.format.extent1383 - 1391
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectChromatin
dc.subjectHumans
dc.subjectOvarian Neoplasms
dc.subjectHistones
dc.subjectChromatin Immunoprecipitation
dc.subjectDNA Methylation
dc.subjectEpigenesis, Genetic
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGene Silencing
dc.subjectHistone Code
dc.subjectCpG Islands
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectPromoter Regions, Genetic
dc.subjectCarcinoma, Ovarian Epithelial
dc.titleGenes Predisposed to DNA Hypermethylation during Acquired Resistance to Chemotherapy Are Identified in Ovarian Tumors by Bivalent Chromatin Domains at Initial Diagnosis.
dc.typeJournal Article
dcterms.dateAccepted2018-01-10
rioxxterms.versionofrecord10.1158/0008-5472.can-17-1650
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-03
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue6
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Medicine (Brown Epigenetic Therapy)
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Medicine (Brown Epigenetic Therapy)
pubs.publication-statusPublished
pubs.volume78
pubs.embargo.termsNot known
icr.researchteamMedicine (Brown Epigenetic Therapy)en_US
dc.contributor.icrauthorBrown, Roberten


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