Genome-wide Estrogen Receptor-α activation is sustained, not cyclical.
eLife Sciences Publications, Ltd
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Holding, A. N., Cullen, A. E., & Markowetz, F. (2018). Genome-wide Estrogen Receptor-α activation is sustained, not cyclical.. Elife, 7 https://doi.org/10.7554/eLife.40854
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.
Humans, Estradiol, Neoplasm Proteins, Estrogen Receptor alpha, Signal Transduction, Gene Expression Regulation, Neoplastic, Binding Sites, Base Sequence, Protein Binding, Genome, Human, Female, Receptors, CXCR, Promoter Regions, Genetic, Genome-Wide Association Study, Sorting Nexins, MCF-7 Cells, Trefoil Factor-1
Breast Cancer Campaign (2012NovemberPR042)
Cancer Research UK (C14303/A17197)
Alan Turing Institute (Unknown)
Cancer Research UK (A19274)
External DOI: https://doi.org/10.7554/eLife.40854
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287052
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/