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ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands

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 el...

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Published in:The EMBO journal 2009-05, Vol.28 (10), p.1418
Main Authors: Welboren, Willem-Jan, van Driel, Marc A, Janssen-Megens, Eva M, van Heeringen, Simon J, Sweep, Fred Cgj, Span, Paul N, Stunnenberg, Hendrik G
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container_issue 10
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container_title The EMBO journal
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creator Welboren, Willem-Jan
van Driel, Marc A
Janssen-Megens, Eva M
van Heeringen, Simon J
Sweep, Fred Cgj
Span, Paul N
Stunnenberg, Hendrik G
description 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.
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subjects Binding Sites
Cell Line
Chromatin Immunoprecipitation
DNA - metabolism
Estradiol - analogs & derivatives
Estradiol - pharmacology
Estrogen Receptor alpha - metabolism
Gene Expression Regulation - drug effects
Humans
Protein Binding
RNA Polymerase II - metabolism
RNA, Messenger - biosynthesis
Selective Estrogen Receptor Modulators - pharmacology
Sequence Analysis, DNA
Tamoxifen - pharmacology
title ChIP-Seq of ERalpha and RNA polymerase II defines genes differentially responding to ligands
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