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The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes

Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in br...

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Autores principales: Jangal, Maïka, Couture, Jean-Philippe, Bianco, Stéphanie, Magnani, Luca, Mohammed, Hisham, Gévry, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191390/
https://www.ncbi.nlm.nih.gov/pubmed/25223786
http://dx.doi.org/10.1093/nar/gku791
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author Jangal, Maïka
Couture, Jean-Philippe
Bianco, Stéphanie
Magnani, Luca
Mohammed, Hisham
Gévry, Nicolas
author_facet Jangal, Maïka
Couture, Jean-Philippe
Bianco, Stéphanie
Magnani, Luca
Mohammed, Hisham
Gévry, Nicolas
author_sort Jangal, Maïka
collection PubMed
description Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation.
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spelling pubmed-41913902015-04-02 The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes Jangal, Maïka Couture, Jean-Philippe Bianco, Stéphanie Magnani, Luca Mohammed, Hisham Gévry, Nicolas Nucleic Acids Res Gene regulation, Chromatin and Epigenetics Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation. Oxford University Press 2014-10-13 2014-09-15 /pmc/articles/PMC4191390/ /pubmed/25223786 http://dx.doi.org/10.1093/nar/gku791 Text en © The Author(s) 2014. 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
Jangal, Maïka
Couture, Jean-Philippe
Bianco, Stéphanie
Magnani, Luca
Mohammed, Hisham
Gévry, Nicolas
The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title_full The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title_fullStr The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title_full_unstemmed The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title_short The transcriptional co-repressor TLE3 suppresses basal signaling on a subset of estrogen receptor α target genes
title_sort transcriptional co-repressor tle3 suppresses basal signaling on a subset of estrogen receptor α target genes
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191390/
https://www.ncbi.nlm.nih.gov/pubmed/25223786
http://dx.doi.org/10.1093/nar/gku791
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