ArticleGenes & development2021
A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in the liver.
Article in Genes & development, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 36 citations in OpenAlex.
- The human THRB thyroid hormone receptor gene and the puzzle of retinal disease phenotypes.Developmental biology · 2026Review
- The impactful role of the HDACs in the regulation of gene expression and as targets for disease therapy.Science advances · 2026Review
- Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes.Nature communications · 2026Article
- Nuclear receptor coregulator interactions: beyond the switch.Genes & development · 2026Review
- SOSHI-seq: a high-throughput screening assay to test the functionality of putative response elements for nuclear hormone receptors.Scientific reports · 2025Article
- Epigenomic Modulators and Thyroid Hormone Receptor β Agonists: A New Paradigm for Tumor Suppression in Thyroid Cancer.Endocrinology · 2025Review
- Transcriptional Cofactors for Thyroid Hormone Receptors.Endocrinology · 2025Review
- Thyroid hormone receptor beta-2 (TRβ2) overexpression modulates photoreceptor phenotype diversity in a ligand-dependent manner.Frontiers in cell and developmental biology · 2025Article
- Thyroid Hormone Action by Genomic and Nongenomic Molecular Mechanisms.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Nuclear receptor corepressor 1 levels differentially impact the intracellular dynamics of mutant thyroid hormone receptors associated with resistance to thyroid hormone syndrome.Molecular and cellular endocrinology · 2024Article
- Functions and Mechanism of Thyroid Hormone Receptor Action During Amphibian Development.Endocrinology · 2024Review
- NCOR1/2 and glucocorticoid receptor orchestrate hepatic function.Nature metabolism · 2024Article
- Metabolic Messengers: Thyroid Hormones.Nature metabolism · 2024Review
- Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice.Scientific reports · 2024Article
- Thyroid hormone-regulated chromatin landscape and transcriptional sensitivity of the pituitary gland.Communications biology · 2023Article
- International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023.Pharmacological reviews · 2023Review
- Plasticity of cone photoreceptors in adult zebrafish revealed by thyroid hormone exposure.Scientific reports · 2023Article
- Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System.International journal of molecular sciences · 2023Review
- The thyroid hormone enhances mouse embryonic fibroblasts reprogramming to pluripotent stem cells: role of the nuclear receptor corepressor 1.Frontiers in endocrinology · 2023Article
- Transcriptional control of energy metabolism by nuclear receptors.Nature reviews. Molecular cell biology · 2022Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
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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