scholarly journals Structure-guided approach to relieving transcriptional repression inResistance to Thyroid Hormone α

2021 ◽  
Author(s):  
Beatriz Romartinez-Alonso ◽  
Maura Agostini ◽  
Heulyn Jones ◽  
Jayde McLellan ◽  
Deepali Sood ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Transcriptional Repression ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Activation Function ◽  
Zebrafish Model ◽  
Target Gene Expression ◽  
Corepressor Complex ◽  
Thyroid Hormone Receptor Α

Mutations in thyroid hormone receptor α (TRα), a ligand-inducible transcription factor, cause Resistance to Thyroid Hormone α (RTHα). This disorder is characterised by tissue-specific hormone refractoriness and hypothyroidism, due to inhibition of target gene expression by mutant TRα-corepressor complexes. Using biophysical approaches, we show that RTHα-associated TRα mutants devoid of ligand-dependent transcription activation function, unexpectedly retain the ability to bind thyroid hormone. Visualisation of ligand (T3) within the crystal structure of a prototypic TRα mutant, validates this notion. This finding prompted synthesis of different thyroid hormone analogues, identifying a lead compound (ES08) which dissociates corepressor from mutant human TRα more efficaciously than T3. ES08 rescues developmental anomalies in a zebrafish model of RTHα and induces target gene expression in TRα mutation-containing cells from an RTHα patient, more effectively than T3. Our observations provide proof-of-principle for developing synthetic ligands that can relieve transcriptional repression by the mutant TRα-corepressor complex, for treatment of RTHα.

scholarly journals Characterization of skeletal phenotypes of TRα1PV and TRβPV mutant mice: implications for tissue thyroid status and T3 target gene expression

2006 ◽  
Vol 4 (1) ◽  
pp. nrs.04011 ◽  
Author(s):  
Patrick J. O'Shea ◽  
J.H. Duncan Bassett ◽  
Sheue-yann Cheng ◽  
Graham R. Williams
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Bone Development ◽  
Negative Resistance ◽  
Dominant Negative ◽  
Thyroid Status ◽  
Target Gene Expression

Bone development is extremely sensitive to alterations in thyroid status. Recently, we analyzed the skeletal phenotypes of mice with the dominant negative resistance to thyroid hormone (RTH) mutation PV targeted to either the thyroid hormone receptor (TR) α1 or β gene. This perspective summarizes our findings to date and explores the wider implications for thyroid status and T3 target gene expression in individual tissues.

scholarly journals Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples of menopausal women

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Sandro José Conde ◽  
Renata de Azevedo M. Luvizotto ◽  
Maria Teresa Síbio ◽  
Célia Regina Nogueira
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Gene ◽  
Target Gene Expression ◽  
Menopausal Women ◽  
Hormone Status

scholarly journals Negative Regulation of TSHα Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation

2009 ◽  
Vol 23 (5) ◽  
pp. 600-609 ◽  
Author(s):  
Dongqing Wang ◽  
Xianmin Xia ◽  
Ying Liu ◽  
Alexis Oetting ◽  
Robert L. Walker ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Histone Acetylation ◽  
Chromatin Immunoprecipitation ◽  
Hormone Receptor ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Critical Role ◽  
Negative Regulation ◽  
Pituitary Cells ◽  
Corepressor Complex

Abstract Currently, little is known about histone modifications and molecular mechanisms of negatively regulated transcription. In pituitary cells, thyroid hormone (T3) decreased transcription, and surprisingly increased histone acetylation, of TSHα promoter. This increase was mediated directly by thyroid hormone receptor. Histone acetylation of H3K9 and H3K18 sites, two modifications usually associated with transcriptional activation, occur in negative regulation of TSHα promoter. T3 also caused release of a corepressor complex composed of histone deacetylase 3 (HDAC3), transducin β-like protein 1, and nuclear receptor coprepressor (NCoR)/ silencing mediator for retinoic and thyroid hormone receptor from TSHα promoter in chromatin immunoprecipitation assays. NCoR and HDAC3 overexpression selectively increased ligand-independent basal transcription. Two histone acetyltransferase inhibitors increased overall transcription but did not abrogate negative regulation or NCoR/HDAC3 complex release by T3. Chromatin immunoprecipitation analyses of an endogenous positively regulated target gene showed increased histone acetylation and corepressor complex release with T3 treatment. Finally, microarray analyses suggested there is a subset of negatively regulated genes with increased histone acetylation. These findings demonstrate the critical role of NCoR/HDAC3 complex in negative regulation of TSHα gene expression and show that similar complexes and overlapping epigenetic modifications can participate in both negative and positive transcriptional regulation.

The corepressor Alien as a novel tumor suppressor?

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Aria Baniahmad
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Gene Silencing ◽  
Hormone Receptor ◽  
Cell Cycle Progression ◽  
Target Gene ◽  
Thyroid Hormone Receptor ◽  
Cycle Progression ◽  
Target Gene Expression ◽  
Proteomic Approach

AbstractAlien has been characterized as a corepressor for nuclear hormone receptors that harbor a silencing domain such as the thyroid hormone receptor (TR), the vitamin D3 receptor (VDR) and DAX-1. In addition, the androgen receptor (AR), a steroid hormone receptor, interacts with Alien. Alien enhances gene silencing mediated by TR, VDR and DAX-1, whereas Alien inhibits AR-mediated transactivation. The inhibition of AR by Alien seems to be restricted to cases where AR is bound to AR antagonists. In line with this, Alien inhibits AR target gene expression and human prostate cancer cell proliferation in an antagonist-specific manner indicating that Alien has an inhibitory role for cell cycle progression. Alien mediates gene silencing by recruitment of histone deacetylase activity and interestingly through nucleo-some assembly activity. Hereby, Alien enhances nucleosome positioning mediated by nucleosome assembly protein 1, which suggests a novel molecular mechanism of corepressor function. Using a proteomic approach to identify Alien interacting partners, we detected the cell cycle factor E2F1 to bind to Alien in vivo. The E2F1-mediated transactivation and E2F target gene expression is inhibited by Alien, and in line with this Alien is observed to repress cell cycle progression.

scholarly journals SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

2021 ◽  
Author(s):  
Ville Paakinaho ◽  
Joanna K Lempiäinen ◽  
Gianluca Sigismondo ◽  
Einari A Niskanen ◽  
Marjo Malinen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Transcriptional Repression ◽  
Target Gene ◽  
Enzyme Inhibitor ◽  
Chromatin Accessibility ◽  
Protein Network ◽  
Chromatin Binding ◽  
Target Gene Expression ◽  
Associated Proteins

Abstract Glucocorticoid receptor (GR) is an essential transcription factor (TF), controlling metabolism, development and immune responses. SUMOylation regulates chromatin occupancy and target gene expression of GR in a locus-selective manner, but the mechanism of regulation has remained elusive. Here, we identify the protein network around chromatin-bound GR by using selective isolation of chromatin-associated proteins and show that the network is affected by receptor SUMOylation, with several nuclear receptor coregulators and chromatin modifiers preferring interaction with SUMOylation-deficient GR and proteins implicated in transcriptional repression preferring interaction with SUMOylation-competent GR. This difference is reflected in our chromatin binding, chromatin accessibility and gene expression data, showing that the SUMOylation-deficient GR is more potent in binding and opening chromatin at glucocorticoid-regulated enhancers and inducing expression of target loci. Blockage of SUMOylation by a SUMO-activating enzyme inhibitor (ML-792) phenocopied to a large extent the consequences of GR SUMOylation deficiency on chromatin binding and target gene expression. Our results thus show that SUMOylation modulates the specificity of GR by regulating its chromatin protein network and accessibility at GR-bound enhancers. We speculate that many other SUMOylated TFs utilize a similar regulatory mechanism.

scholarly journals Thyroid Hormone Status Interferes with Estrogen Target Gene Expression in Breast Cancer Samples in Menopausal Women

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sandro José Conde ◽  
Renata de Azevedo Melo Luvizotto ◽  
Maria Teresa de Síbio ◽  
Célia Regina Nogueira
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Gene ◽  
Progesterone Receptors ◽  
Control Group ◽  
Target Gene Expression ◽  
Menopausal Women ◽  
Hormone Status ◽  
Before And After

We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues. We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC. We measured serum TPO-AB, TSH, FT4, and estradiol, before and after surgery, and used immunohistochemistry to examine estrogen and progesterone receptors. BrC primary tissue cultures received the following treatments: ethanol, triiodothyronine, triiodothyronine plus 4-hydroxytamoxifen, 4-hydroxytamoxifen, estrogen, or estrogen plus 4-hydroxytamoxifen. Genes regulated by estrogen (TGFA, TGFB1, and PGR) and by triiodothyronine (TNFRSF9, BMP-6, and THRA) in vitro were evaluated. TSH levels in BrC patients did not differ from those of the control group (1.34 ± 0.60 versus 2.41 ± 1.10 μU/mL), but FT4 levels of BrC patients were statistically higher than controls (1.78 ± 0.20 versus 0.95 ± 0.16 ng/dL). TGFA was upregulated and downregulated after estrogen and triiodothyronine treatment, respectively. Triiodothyronine increased PGR expression; however 4-hydroxytamoxifen did not block triiodothyronine action on PGR expression. 4-Hydroxytamoxifen, alone or associated with triiodothyronine, modulated gene expression of TNFRSF9, BMP-6, and THRA, similar to triiodothyronine treatment. Thus, our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women.

scholarly journals 351. Inhibition of Thyroid Hormone Receptors in the Neural Stem Cells of Newborn and Adult Mice In Vivo: Consequences on Target Gene Expression

2006 ◽  
Vol 13 ◽  
pp. S134
Author(s):  
Zahra Hassani ◽  
Gladys Alfama ◽  
Jean-Christophe François ◽  
Carinne Giovannangeli ◽  
Barbara A. Demeneix
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Thyroid Hormone ◽  
Neural Stem Cells ◽  
Target Gene ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Target Gene Expression ◽  
Adult Mice
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