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A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver

Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor to...

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Autores principales: Shabtai, Yehuda, Nagaraj, Nagaswaroop K., Batmanov, Kirill, Cho, Young-Wook, Guan, Yuxia, Jiang, Chunjie, Remsberg, Jarrett, Forrest, Douglas, Lazar, Mitchell A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919419/
https://www.ncbi.nlm.nih.gov/pubmed/33602873
http://dx.doi.org/10.1101/gad.345686.120
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author Shabtai, Yehuda
Nagaraj, Nagaswaroop K.
Batmanov, Kirill
Cho, Young-Wook
Guan, Yuxia
Jiang, Chunjie
Remsberg, Jarrett
Forrest, Douglas
Lazar, Mitchell A.
author_facet Shabtai, Yehuda
Nagaraj, Nagaswaroop K.
Batmanov, Kirill
Cho, Young-Wook
Guan, Yuxia
Jiang, Chunjie
Remsberg, Jarrett
Forrest, Douglas
Lazar, Mitchell A.
author_sort Shabtai, Yehuda
collection PubMed
description Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.
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spelling pubmed-79194192021-09-01 A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver Shabtai, Yehuda Nagaraj, Nagaswaroop K. Batmanov, Kirill Cho, Young-Wook Guan, Yuxia Jiang, Chunjie Remsberg, Jarrett Forrest, Douglas Lazar, Mitchell A. Genes Dev Research Paper Thyroid hormones (THs) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone-dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TRs), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR and defined high-confidence binding sites where TRs functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by THs have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, THs regulate gene expression by orchestrating a shift in the relative binding of corepressors and coactivators. Cold Spring Harbor Laboratory Press 2021-03-01 /pmc/articles/PMC7919419/ /pubmed/33602873 http://dx.doi.org/10.1101/gad.345686.120 Text en © 2021 Shabtai et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Shabtai, Yehuda
Nagaraj, Nagaswaroop K.
Batmanov, Kirill
Cho, Young-Wook
Guan, Yuxia
Jiang, Chunjie
Remsberg, Jarrett
Forrest, Douglas
Lazar, Mitchell A.
A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title_full A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title_fullStr A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title_full_unstemmed A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title_short A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
title_sort coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919419/
https://www.ncbi.nlm.nih.gov/pubmed/33602873
http://dx.doi.org/10.1101/gad.345686.120
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