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Regulatory sharing between estrogen receptor α bound enhancers

The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers exhibit complex synergistic contributions to th...

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Autores principales: Carleton, Julia B, Ginley-Hidinger, Matthew, Berrett, Kristofer C, Layer, Ryan M, Quinlan, Aaron R, Gertz, Jason
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337896/
https://www.ncbi.nlm.nih.gov/pubmed/32479598
http://dx.doi.org/10.1093/nar/gkaa454
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author Carleton, Julia B
Ginley-Hidinger, Matthew
Berrett, Kristofer C
Layer, Ryan M
Quinlan, Aaron R
Gertz, Jason
author_facet Carleton, Julia B
Ginley-Hidinger, Matthew
Berrett, Kristofer C
Layer, Ryan M
Quinlan, Aaron R
Gertz, Jason
author_sort Carleton, Julia B
collection PubMed
description The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of this enhancer cooperativity. We generated genetic deletions of four estrogen receptor α (ER) bound enhancers that regulate two genes and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences, we found that the genomic location of a full ERE strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of a pre-existing permissible chromatin environment can also be needed for estrogen-driven gene regulation to occur.
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spelling pubmed-73378962020-07-13 Regulatory sharing between estrogen receptor α bound enhancers Carleton, Julia B Ginley-Hidinger, Matthew Berrett, Kristofer C Layer, Ryan M Quinlan, Aaron R Gertz, Jason Nucleic Acids Res Gene regulation, Chromatin and Epigenetics The human genome encodes an order of magnitude more gene expression enhancers than promoters, suggesting that most genes are regulated by the combined action of multiple enhancers. We have previously shown that neighboring estrogen-responsive enhancers exhibit complex synergistic contributions to the production of an estrogenic transcriptional response. Here we sought to determine the molecular underpinnings of this enhancer cooperativity. We generated genetic deletions of four estrogen receptor α (ER) bound enhancers that regulate two genes and found that enhancers containing full estrogen response element (ERE) motifs control ER binding at neighboring sites, while enhancers with pre-existing histone acetylation/accessibility confer a permissible chromatin environment to the neighboring enhancers. Genome engineering revealed that two enhancers with half EREs could not compensate for the lack of a full ERE site within the cluster. In contrast, two enhancers with full EREs produced a transcriptional response greater than the wild-type locus. By swapping genomic sequences, we found that the genomic location of a full ERE strongly influences enhancer activity. Our results lead to a model in which a full ERE is required for ER recruitment, but the presence of a pre-existing permissible chromatin environment can also be needed for estrogen-driven gene regulation to occur. Oxford University Press 2020-07-09 2020-06-01 /pmc/articles/PMC7337896/ /pubmed/32479598 http://dx.doi.org/10.1093/nar/gkaa454 Text en © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Carleton, Julia B
Ginley-Hidinger, Matthew
Berrett, Kristofer C
Layer, Ryan M
Quinlan, Aaron R
Gertz, Jason
Regulatory sharing between estrogen receptor α bound enhancers
title Regulatory sharing between estrogen receptor α bound enhancers
title_full Regulatory sharing between estrogen receptor α bound enhancers
title_fullStr Regulatory sharing between estrogen receptor α bound enhancers
title_full_unstemmed Regulatory sharing between estrogen receptor α bound enhancers
title_short Regulatory sharing between estrogen receptor α bound enhancers
title_sort regulatory sharing between estrogen receptor α bound enhancers
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337896/
https://www.ncbi.nlm.nih.gov/pubmed/32479598
http://dx.doi.org/10.1093/nar/gkaa454
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