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Publication year
2009Source
EMBO Journal, 28, 10, (2009), pp. 1418-28ISSN
Publication type
Article / Letter to editor

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Organization
Laboratory of Genetic, Endocrine and Metabolic Diseases
CMBI
Molecular Biology
Chemical Endocrinology
Radiation Oncology
Former Organization
Bioinformatics (umcn)
Journal title
EMBO Journal
Volume
vol. 28
Issue
iss. 10
Page start
p. 1418
Page end
p. 28
Subject
IGMD 6: Hormonal regulation; Molecular Biology; NCMLS 6: Genetics and epigenetic pathways of disease; ONCOL 1: Hereditary cancer and cancer-related syndromes; ONCOL 3: Translational research; ONCOL 5: Aetiology, screening and detectionAbstract
We used ChIP-Seq to map ERalpha-binding sites and to profile changes in RNA polymerase II (RNAPII) occupancy in MCF-7 cells in response to estradiol (E2), tamoxifen or fulvestrant. We identify 10 205 high confidence ERalpha-binding sites in response to E2 of which 68% contain an estrogen response element (ERE) and only 7% contain a FOXA1 motif. Remarkably, 596 genes change significantly in RNAPII occupancy (59% up and 41% down) already after 1 h of E2 exposure. Although promoter proximal enrichment of RNAPII (PPEP) occurs frequently in MCF-7 cells (17%), it is only observed on a minority of E2-regulated genes (4%). Tamoxifen and fulvestrant partially reduce ERalpha DNA binding and prevent RNAPII loading on the promoter and coding body on E2-upregulated genes. Both ligands act differently on E2-downregulated genes: tamoxifen acts as an agonist thus downregulating these genes, whereas fulvestrant antagonizes E2-induced repression and often increases RNAPII occupancy. Furthermore, our data identify genes preferentially regulated by tamoxifen but not by E2 or fulvestrant. Thus (partial) antagonist loaded ERalpha acts mechanistically different on E2-activated and E2-repressed genes.
This item appears in the following Collection(s)
- Academic publications [227436]
- Electronic publications [107268]
- Faculty of Medical Sciences [86157]
- Faculty of Science [33757]
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