Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
- University of Cambridge, United Kingdom
Abstract
Estrogen 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.
Data availability
Sequencing data have been deposited in GEO under accession code GSE119057.
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Genome-wide Estrogen Receptor-alpha activation time-courseGene Expression Omnibus, GSE119057.
Article and author information
Author details
Funding
Cancer Research UK (C14303/A17197)
- Florian Markowetz
Breast Cancer Now (2012NovPR042)
- Florian Markowetz
Cancer Research UK (C60571/A24631)
- Andrew N Holding
Cancer Research UK (A19274)
- Florian Markowetz
Alan Turing Institute (EPSRC grant EP/N510129/129/1)
- Andrew N Holding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Holding et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
eLife 7:e40854.
https://doi.org/10.7554/eLife.40854
