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Elife. 2018 Nov 20;7. pii: e40854. doi: 10.7554/eLife.40854.

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

Author information

1
Cancer Research UK Cambridge Institute, University of Cambridge, 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.

KEYWORDS:

Estrogen; Estrogen Receptor; MCF7; breast Cancer; chromosomes; computational biology; endocrine; gene expression; human; systems biology

PMID:
30457555
PMCID:
PMC6287946
DOI:
10.7554/eLife.40854
[Indexed for MEDLINE]
Free PMC Article

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