The functional relationship between co-repressor N-CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor α

2008 ◽  
Vol 411 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Kyung-Chul Choi ◽  
So-Young Oh ◽  
Hee-Bum Kang ◽  
Yoo-Hyun Lee ◽  
Seungjoo Haam ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Fatty Acid Synthase ◽  
Hormone Receptors ◽  
Target Genes ◽  
Functional Relationship ◽  
Thyroid Hormone Receptor ◽  
B Cell Lymphoma ◽  
Hormone Response Elements

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.

scholarly journals Molecular cloning and characterization of thyroid hormone receptors in teleost fish

2001 ◽  
Vol 26 (1) ◽  
pp. 51-65 ◽  
Author(s):  
O Marchand ◽  
R Safi ◽  
H Escriva ◽  
E Van Rompaey ◽  
P Prunet ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Teleost Fish ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Hormone Response Elements ◽  
Reverse Transcription Pcr ◽  
Wide Range

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.

The functional relationship between corepressor N‐CoR and SMRT in mediating transcriptional repression by thyroid hormone receptor alpha

2008 ◽  
Vol 22 (S2) ◽  
pp. 201-201
Author(s):  
Kyung‐Chul Choi ◽  
Hyo‐Kyoung Choi ◽  
Hee‐Bum Kang ◽  
Yoo‐Hyun Lee ◽  
Jung‐Yoon Yoo ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Transcriptional Repression ◽  
Functional Relationship ◽  
Thyroid Hormone Receptor ◽  
Receptor Alpha

scholarly journals Identification of thyroid hormone response elements in vivo using mice expressing a tagged thyroid hormone receptor α1

2013 ◽  
Vol 33 (2) ◽  
Author(s):  
Susi Dudazy-Gralla ◽  
Kristina Nordström ◽  
Peter Josef Hofmann ◽  
Dina Abdul Meseh ◽  
Lutz Schomburg ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Hormone Response ◽  
Protein Fusion ◽  
Response Elements ◽  
Hormone Response Elements

TRα1 (thyroid hormone receptor α1) is well recognized for its importance in brain development. However, due to the difficulties in predicting TREs (thyroid hormone response elements) in silico and the lack of suitable antibodies against TRα1 for ChIP (chromatin immunoprecipitation), only a few direct TRα1 target genes have been identified in the brain. Here we demonstrate that mice expressing a TRα1–GFP (green fluorescent protein) fusion protein from the endogenous TRα locus provide a valuable animal model to identify TRα1 target genes. To this end, we analysed DNA–TRα1 interactions in vivo using ChIP with an anti-GFP antibody. We validated our system using established TREs from neurogranin and hairless, and by verifying additional TREs from known TRα1 target genes in brain and heart. Moreover, our model system enabled the identification of novel TRα1 target genes such as RNF166 (ring finger protein 166). Our results demonstrate that transgenic mice expressing a tagged nuclear receptor constitute a feasible approach to study receptor–DNA interactions in vivo, circumventing the need for specific antibodies. Models like the TRα1–GFP mice may thus pave the way for genome-wide mapping of nuclear receptor-binding sites, and advance the identification of novel target genes in vivo.

scholarly journals Marked Potentiation of the Dominant Negative Action of a Mutant Thyroid Hormone Receptor β in Mice by the Ablation of One Wild-Type β Allele

2003 ◽  
Vol 17 (5) ◽  
pp. 895-907 ◽  
Author(s):  
H. Suzuki ◽  
X.-Y. Zhang ◽  
D. Forrest ◽  
M. C. Willingham ◽  
S.-Y. Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Hormone Response Elements ◽  
Papillary Hyperplasia

Abstract Mutations in the thyroid hormone receptor (TR) β gene result in resistance to thyroid hormone (RTH), characterized by reduced sensitivity of tissues to thyroid hormone. To understand which physiological TR pathways are affected by mutant receptors, we crossed mice with a dominantly negative TRβ mutation (TRβPV) with mice carrying a TRβ null mutation (TRβ−/−) to determine the consequences of the TRβPV mutation in the absence of wild-type TRβ. TRβPV/− mice are distinct from TRβ+/− mice that did not show abnormalities in thyroid function tests. TRβPV/− mice are also distinct from TRβPV/+ and TRβ−/− mice in that the latter shows mild dysfunction in the pituitary-thyroid axis, whereas the former exhibit very severe abnormalities, including extensive papillary hyperplasia of the thyroid epithelium, indistinguishable from that observed in TRβPV/PV mice. Similar to TRβPV/PV mice, TRβPV/− mice exhibited impairment in weight gain. Moreover, the abnormal regulation patterns of T3-target genes in the tissues of TRβPV/− and TRβPV/PV mice were strikingly similar. Using TR isoforms and PV-specific antibodies in gel shift assays, we found that in vivo, PV competed with TRα1 for binding to thyroid hormone response elements in TRβPV/− mice as effectively as in TRβPV/PV mice. Thus, the actions of mutant TRβ are markedly potentiated by the ablation of the second TRβ allele, suggesting that interference with wild-type TRα1-mediated gene regulation by mutant TRβ leads to severe RTH.

scholarly journals The thyroid hormone receptor gene (c-erbA alpha) is expressed in advance of thyroid gland maturation during the early embryonic development of Xenopus laevis.

1991 ◽  
Vol 11 (10) ◽  
pp. 5079-5089 ◽  
Author(s):  
D E Banker ◽  
J Bigler ◽  
R N Eisenman
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Xenopus Laevis ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Stages Of Development ◽  
Xenopus Development

The c-erbA proto-oncogene encodes the thyroid hormone receptor, a ligand-dependent transcription factor which plays an important role in vertebrate growth and development. To define the role of the thyroid hormone receptor in developmental processes, we have begun studying c-erbA gene expression during the ontogeny of Xenopus laevis, an organism in which thyroid hormone has well-documented effects on morphogenesis. Using polymerase chain reactions (PCR) as a sensitive assay of specific gene expression, we found that polyadenylated erbA alpha RNA is present in Xenopus cells at early developmental stages, including the fertilized egg, blastula, gastrula, and neurula. By performing erbA alpha-specific PCR on reverse-transcribed RNAs from high-density sucrose gradient fractions prepared from early-stage embryos, we have demonstrated that these erbA transcripts are recruited to polysomes. Therefore, erbA is expressed in Xenopus development prior to the appearance of the thyroid gland anlage in tailbud-stage embryos. This implies that erbA alpha/thyroid hormone receptors may play ligand-independent roles during the early development of X. laevis. Quantitative PCR revealed a greater than 25-fold range in the steady-state levels of polyadenylated erbA alpha RNA across early stages of development, as expressed relative to equimolar amounts of total embryonic RNA. Substantial increases in the levels of erbA alpha RNA were noted at stages well after the onset of zygotic transcription at the mid-blastula transition, with accumulation of erbA alpha transcripts reaching a relative maximum in advance of metamorphosis. We also show that erbA alpha RNAs are expressed unequally across Xenopus neural tube embryos. This differential expression continues through later stages of development, including metamorphosis. This finding suggests that erbA alpha/thyroid hormone receptors may play roles in tissue-specific processes across all of Xenopus development.

scholarly journals In Vivo Activity of the Thyroid Hormone Receptor β- and α-Selective Agonists GC-24 and CO23 on Rat Liver, Heart, and Brain

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1136-1142 ◽  
Author(s):  
Carmen Grijota-Martínez ◽  
Eric Samarut ◽  
Thomas S. Scanlan ◽  
Beatriz Morte ◽  
Juan Bernal
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Genetic Modifications ◽  
Hormone Analogs ◽  
Thyroid Hormone Receptor Β

Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRβ-selective GC-24 and the TRα-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRβ and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRα or TRβ. This compound, previously shown to be TRα-selective in tadpoles, displayed no selectivity in the rat in vivo.

Abstract P244: Transcriptional Regulation of Cardiac Gene Expression by Med13 Alters Global Energy Balance

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Chad E Grueter ◽  
Brett A Johnson ◽  
Xiaoxia Qi ◽  
John McAnally ◽  
Rhonda Bassel-Duby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Cardiac Contractility ◽  
Nuclear Hormone Receptor ◽  
Mediator Complex

Aberrant cardiac metabolism is associated with obesity, type 2 diabetes and heart failure. The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function, however little is known about the role of the heart as a metabolic organ. Nuclear hormone receptors, such as thyroid hormone receptor play an important role in cardiovascular disease by significantly altering expression of genes involved in maintaining metabolic activity. The Mediator, a large multiprotein complex functions as a hub to control gene expression through association with transcriptional activators and repressors. We tested the hypothesis that Med13, a component of the Mediator complex, regulates cardiac function in a gain-of-function mouse model. Trangsenic mice overexpressing Med13 in the heart are lean, have increased energy expenditure, are resistant to high fat diet-induced obesity and have enhanced cardiac contractility. Microarray analysis and biochemical assays show that in vivo and in vitro Med13 selectively inhibits nuclear hormone receptor target genes of energy metabolism. These results implicate the Mediator complex regulates energy balance and cardiac contractility and suggests that the heart may function as a key component of mammalian energy homeostasis.

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