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

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 w...

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Detalles Bibliográficos
Autores principales: Holding, Andrew N, Cullen, Amy E, Markowetz, Florian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287946/
https://www.ncbi.nlm.nih.gov/pubmed/30457555
http://dx.doi.org/10.7554/eLife.40854
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author Holding, Andrew N
Cullen, Amy E
Markowetz, Florian
author_facet Holding, Andrew N
Cullen, Amy E
Markowetz, Florian
author_sort Holding, Andrew N
collection PubMed
description 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.
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spelling pubmed-62879462018-12-13 Genome-wide Estrogen Receptor-α activation is sustained, not cyclical Holding, Andrew N Cullen, Amy E Markowetz, Florian eLife Chromosomes and Gene Expression 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. eLife Sciences Publications, Ltd 2018-11-20 /pmc/articles/PMC6287946/ /pubmed/30457555 http://dx.doi.org/10.7554/eLife.40854 Text en © 2018, Holding et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Chromosomes and Gene Expression
Holding, Andrew N
Cullen, Amy E
Markowetz, Florian
Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title_full Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title_fullStr Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title_full_unstemmed Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title_short Genome-wide Estrogen Receptor-α activation is sustained, not cyclical
title_sort genome-wide estrogen receptor-α activation is sustained, not cyclical
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287946/
https://www.ncbi.nlm.nih.gov/pubmed/30457555
http://dx.doi.org/10.7554/eLife.40854
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