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Genome-wide Estrogen Receptor-α activation is sustained, not cyclical.

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cam.issuedOnline2018-11-20
dc.contributor.authorHolding, Andrew N
dc.contributor.authorCullen, Amy E
dc.contributor.authorMarkowetz, Florian
dc.contributor.orcidHolding, Andrew N [0000-0002-8459-7048]
dc.contributor.orcidCullen, Amy E [0000-0002-5015-1355]
dc.contributor.orcidMarkowetz, Florian [0000-0002-2784-5308]
dc.date.accessioned2018-12-18T00:31:18Z
dc.date.available2018-12-18T00:31:18Z
dc.date.issued2018-11-20
dc.description.abstractEstrogen Receptor-alpha (ER) drives 75% of breast cancers. Stimulation of the ER by estra-2-diol forms a transcriptionally-active chromatin-bound complex. Previous studies reported that ER binding follows a cyclical pattern. However, most studies have been limited to individual ER target genes and without replicates. Thus, the robustness and generality of ER cycling are not well understood. We present a comprehensive genome-wide analysis of the ER after activation, based on 6 replicates at 10 time-points, using our method for precise quantification of binding, Parallel-Factor ChIP-seq. In contrast to previous studies, we identified a sustained increase in affinity, alongside a class of estra-2-diol independent binding sites. Our results are corroborated by quantitative re-analysis of multiple independent studies. Our new model reconciles the conflicting studies into the ER at the TFF1 promoter and provides a detailed understanding in the context of the ER's role as both the driver and therapeutic target of breast cancer.
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.34362
dc.identifier.eissn2050-084X
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287052
dc.languageeng
dc.language.isoeng
dc.publishereLife Sciences Publications, Ltd
dc.publisher.urlhttp://dx.doi.org/10.7554/elife.40854
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectEstrogen
dc.subjectEstrogen Receptor
dc.subjectMCF7
dc.subjectbreast Cancer
dc.subjectchromosomes
dc.subjectcomputational biology
dc.subjectendocrine
dc.subjectgene expression
dc.subjecthuman
dc.subjectsystems biology
dc.subjectBase Sequence
dc.subjectBinding Sites
dc.subjectEstradiol
dc.subjectEstrogen Receptor alpha
dc.subjectFemale
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenome, Human
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectMCF-7 Cells
dc.subjectNeoplasm Proteins
dc.subjectPromoter Regions, Genetic
dc.subjectProtein Binding
dc.subjectReceptors, CXCR
dc.subjectSignal Transduction
dc.subjectSorting Nexins
dc.subjectTrefoil Factor-1
dc.titleGenome-wide Estrogen Receptor-α activation is sustained, not cyclical.
dc.typeArticle
dcterms.dateAccepted2018-11-16
prism.publicationDate2018
prism.publicationNameElife
prism.volume7
pubs.funder-project-idBreast Cancer Campaign (2012NovemberPR042)
pubs.funder-project-idCancer Research UK (C14303/A17197)
pubs.funder-project-idAlan Turing Institute (Unknown)
pubs.funder-project-idCancer Research UK (A19274)
rioxxterms.licenseref.startdate2018-11-20
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.7554/eLife.40854

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