Through Thyroid Hormone Receptors Research Articles

A New Perspective on Thyroid Hormones: Crosstalk with Reproductive Hormones in Females.

Accumulating evidence has shown that thyroid hormones (THs) are vital for female reproductive system homeostasis. THs regulate the reproductive functions through thyroid hormone receptors (THRs)-mediated genomic- and integrin-receptor-associated nongenomic mechanisms, depending on TH ligand status and DNA level, as well as transcription and extra-nuclear signaling transduction activities. These processes involve the binding of THs to intracellular THRs and steroid hormone receptors or membrane receptors and the recruitment of hormone-response elements. In addition, THs and other reproductive hormones can activate common signaling pathways due to their structural similarity and shared DNA consensus sequences among thyroid, peptide, and protein hormones and their receptors, thus constituting a complex and reciprocal interaction network. Moreover, THs not only indirectly affect the synthesis, secretion, and action of reproductive hormones, but are also regulated by these hormones at the same time. This crosstalk may be one of the pivotal factors regulating female reproductive behavior and hormone-related diseases, including tumors. Elucidating the interaction mechanism among the aforementioned hormones will contribute to apprehending the etiology of female reproductive diseases, shedding new light on the treatment of gynecological disorders.

3,5-Diiodothyronine: A Novel Thyroid Hormone Metabolite and Potent Modulator of Energy Metabolism.

Over 30 years of research has demonstrated that 3,5-diiodo-L-thyronine (3,5-T2), an endogenous metabolite of thyroid hormones, exhibits interesting metabolic activities. In rodent models, exogenously administered 3,5-T2 rapidly increases resting metabolic rate and elicits short-term beneficial hypolipidemic effects; however, very few studies have evaluated the effects of endogenous and exogenous T2 in humans. Further analyses on larger cohorts are needed to determine whether 3,5-T2 is a potent additional modulator of energy metabolism. In addition, while several lines of evidence suggest that 3,5-T2 mainly acts through Thyroid hormone receptors (THRs)- independent ways, with mitochondria as a likely cellular target, THRs-mediated actions have also been described. The detailed cellular and molecular mechanisms through which 3,5-T2 elicits a multiplicity of actions remains unknown. Here, we provide an overview of the most recent literature on 3,5-T2 bioactivity with a particular focus on short-term and long-term effects, describing data obtained through in vivo and in vitro approaches in both mammalian and non-mammalian species.

RXR Ligands Modulate Thyroid Hormone Signaling Competence in Young Xenopus laevis Tadpoles.

Appropriate thyroid hormone (TH) signaling through thyroid hormone receptors (TRs) is essential for vertebrate development. Amphibian metamorphosis is initiated and sustained through the action of TH on TRs, which are conserved across vertebrates. TRs heterodimerize with retinoid X receptors (RXRs) on thyroid hormone response elements (TREs) in the genome; however, in most cell line and adult animal studies, RXR ligands do not affect expression of TR target genes. We used a quantitative, precocious metamorphosis assay to interrogate the effects of the RXR agonist bexarotene (Bex) and the RXR antagonist UVI 3003 (UVI) on T3-induced resorption phenotypes in Xenopus laevis tadpoles 1 week postfertilization. Bex potentiated gill and tail resorption, and UVI abrogated T3 action. These results held in transgenic tadpoles bearing a TRE-driven luciferase reporter. Therefore, we used poly-A-primed RNA sequencing transcriptomic analysis to determine their effects on T3-induced gene expression. We also assayed the environmental pollutant tributyltin (TBT), which is an RXR agonist. We found that the proteases that carry out resorption were potentiated by Bex and TBT but were not significantly inhibited by UVI. However, several transcription factors from multiple families (sox4, fosl2, mxd1, mafb, nfib) were all inhibited by UVI and potentiated by Bex and TBT. All required T3 for induction. Time course analysis of gene expression showed that although the agonists could potentiate within 12 hours, the antagonist response lagged. These data indicate that the agonists and antagonist are not necessarily functioning through the same mechanism and suggest that RXR liganding may modulate TH competence in metamorphic signaling.

Thyroid Hormone Signaling in Retinal Development, Survival, and Disease.

Thyroid hormone (TH) is essential in numerous physiological functions and developmental processes. It acts through TH receptors (TRs) to regulate gene expression. The retina is the light-sensitive tissue lining the back of the eye and functions as the first step of the visual process. Rod and cone photoreceptors are specialized sensory neurons in the retina that initiate phototransduction. Rods are responsible for dim light vision, whereas cones are responsible for daytime vision, color vision, and visual acuity. TH signaling regulates retinal development and maintenance. The requirement of TH signaling is typically manifested as its regulation in the cone maturation and expression of the light-sensing pigment protein (cone opsin). There are two components of this regulation. First, TRβ2, a TH-activated transcription factor, is expressed in immature cones and regulates cone differentiation and cone opsin expression; activation of TRβ2 suppresses the expression of short-wave-sensitive opsin 1, induces the expression of medium-wave-sensitive opsin 1, and promotes dorsal-ventral opsin patterning. Second, hypothyroid mouse models display abnormalities in cone opsin expression, supporting the necessity of TH itself in retinal development. TH has been linked to photoreceptor survival. Excessive TH signaling leads to death of developing photoreceptors in healthy and diseased retina, whereas suppressing TH signaling preserves cones in mouse models of retinal degeneration. Some eye diseases, including age-related macular degeneration, have been associated with elevated circulation TH levels. Future work should aim to better understand how TH regulates retinal development, functionality, and survival, to examine the role of TH signaling in the pathogenesis of retinal degeneration, and to explore the potential of TH signaling manipulation for photoreceptor protection. Hopefully, these knowledge bases will lead to the identification of novel strategies for retinal disease prevention and management.

Thyroid hormones and browning of adipose tissue

Thyroid hormone (TH) disorders are associated with profound changes in whole body energy metabolism. A major TH target is thermogenic brown adipose tissue (BAT), which can be stimulated directly through thyroid hormone receptors (TRs) expressed in brown adipocytes and indirectly, through TRs expressed in hypothalamic neurons. White adipose tissue (WAT) adopts BAT characteristics by a diverse range of stimuli in a process referred to as browning. It is now understood that TH also induce WAT browning through peripheral and central mechanisms. In this review, we discuss evidence from animal and human studies that TH disorders are associated with changes in both BAT thermogenesis and WAT browning, thereby influencing body temperature and body weight regulation.

RNA polymerase II phosphorylation at serine 2 and histone H3 tri-methylation at lysine 36 are key steps for thyroid hormone receptor β gene activation by thyroid hormone in Rana catesbeiana tadpole liver

Thyroid hormone (TH) is essential for amphibian metamorphosis, during which the expression of many genes is controlled directly or indirectly through TH receptors (TRs). Thyroid hormone binding to TRs induces coregulator switching on regulatory regions of TH-inducible genes: corepressors complexed with unliganded TRs are replaced by coactivators complexed with liganded TR resulting in transcriptionally active states. The coregulator switching is linked to histone acetylation. In our study, we have investigated the acetylation and methylation states of histones H3 and H4 using chromatin immunoprecipitation (ChIP) assays on the 5′ coding region of the TRβ gene, a primary TH-response gene, in the liver from Rana catesbeiana tadpoles either treated with or not treated with 3,3′,5-triiodothyronine (T3). 3,3′,5-Triiodothyronine treatment for 3days increased the amount of TRβ transcript by 19-fold. This increase was associated with increases in the acetylation of histone H4 and lysine 9 in histone H3 (H3-K9), and tri-methylation of lysine 36 in histone H3 (H3-K36). In addition, the amounts of RNA polymerase II (PolII) and serine 2 phosphorylation in PolII (PolII-S2) increased. These results suggest that T3 treatment enhances the elongation activity of PolII on the TRβ gene in the liver by increasing histone H3-K36 tri-methylation through PolII-S2 phosphorylation.

An Investigation of the DNA Binding Patterns of Thyroid Hormone Receptor

Thyroid hormone mediates a variety of physiological effects through thyroid hormone receptors (TR). Because of the diversity of thyroid hormone response elements (TREs) bound by TR, it is difficult to predict genomic regions regulated by TR ab initio. In this study, we have performed a comprehensive analysis of TR bindign sites in the genome using a novel chromatin IP-Sequencing strategy, employing a biotinylated epitope tag ( BioChIP-Seq). Using this strategy, we have discovered that thyroid hormone receptor binds to a wider diversity of promoter sequences than expected and exhibits unexpected changes in response to hormone binding.

Disruption of Thyroid Hormone Function by Environmental Pollutants

Ag reat number of synthetic chemicals are released into the environment, many of which are known or thought to interfere with normal thyroid hormone (TH) function. THs play important roles in regulating growth and development and maintaining metabolic homeostasis. For example, amphibian tadpole metamorphosis is a TH-triggered and controlled developmental process, and has proven to be useful as a screening tool for environmental pollutants suspected of disrupting TH functions. TH disruption is thought to be caused through a variety of mechanisms, including increased thyroxine (T4 )m etabolism by uridine diphosphate glucuronyl transferases (UDPGTs), blocking TH signaling through TH receptors (TRs), and inductio no fm itochondrial membrane permeability transition (MPT). As our knowledge concerning the specific effects of these chemicals is very limited, further research is needed to obtain accurate informatio nt ob eu se di ne stablishing guidelines for the protection of health in humans and wildlife.

Thyroid hormone regulation of a transcriptional coactivator in Xenopus laevis: Implication for a role in postembryonic tissue remodeling

Thyroid hormone (TH) affects biological processes by regulating gene transcription through TH receptors (TRs). In the presence of TH, TR activates target gene transcription by recruiting one or more transcription coactivators belonging to diverse groups. Here, we demonstrate that during TH-dependent anuran metamorphosis, one such coactivator gene, the Xenopus laevis homolog of human Trip7, is up-regulated by TH. Kinetic studies suggest that Xenopus Trip7 is most likely induced indirectly by TH in a tissue-dependent manner. In the intestine, which undergoes extensive remodeling as the animal changes from being herbivorous to carnivorous, Trip7 is expressed at high levels during but not before or after metamorphosis. It is also up-regulated in other growing or remodeling tissues such as the brain and limb but not in degenerating tadpole tail skin. By using frog oocyte as a model, we show that Trip7 influences basal transcription in a chromatin structure-dependent manner but enhances the function of liganded TR regardless of the chromatin structure of the target promoter. In vitro studies indicate that Trip7 interacts directly with TR. These results suggest that during Xenopus metamorphosis, TH up-regulates, albeit indirectly, Trip7 to enhance TR function during larval-to-adult tissue transformation.

Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis.

Anuran metamorphosis involves systematic transformations of individual organs in a thyroid hormone (TH)-dependent manner. Morphological and cellular studies have shown that the removal of larval organs/tissues such the tail and the tadpole intestinal epithelium is through programmed cell death or apoptosis. Recent molecular investigations suggest that TH regulates metamorphosis by regulating target gene expression through thyroid hormone receptors (TRs), which are DNA-binding transcription factors. Cloning and characterization of TH response genes show that diverse groups of early response genes are induced by TH. The products of these TH response genes are believed to directly or indirectly affect the expression and/or functions of cell death genes, which are conserved at both sequence and function levels in different animal species. A major challenge for future research lies at determining the signaling pathways leading to the activation of apoptotic processes and whether different death genes are involved in the regulation of apoptosis in different tissues/organs to effect tissue-specific transformations.

Oct-1, silencer sequence, and GC box regulate thyroid hormone receptor β1 promoter

Thyroid hormone, acting through thyroid hormone receptors (TRs), plays a crucial role in brain development and its insufficiency results in irreversible brain damage. TR α mRNA is expressed continuously from early embryonic stages, but the level of TR β1 mRNA in brain is more abundant in adult than in fetus. To identify important factors which regulate TR β1 expression, we compared mouse fetal and adult brain nuclear extracts by DNase I footprinting and electrophoretic gel mobility shift assays (EMSA) of the TR β1 promoter. We carried out transient transfection studies in COS 1 cells using the TR β1 promoter fused to Luciferase gene, and used mutated promoter vectors and various expression vectors. In DNase I footprinting using the fragment -950 to -717, fetal brain nuclear extracts protected the areas -910 to -884 and -815 to -800 more than did adult extracts. In EMSA, proteins in fetal nuclear extracts bound to a silencer sequence (−924 to -916), GC box (−901 to -887), and E box (−810 to -805), more strongly than did proteins in adult brain extracts. The bands formed on GC box were not supershifted by Sp-1, Sp-2, Sp-3, Sp-4, EGR-1, or EGR-2 antibodies. Three bands were detected on the octamer binding site probe (−913 to -906) and one protein was supershifted by Oct-1 antibody. Adult brain extracts appear to contain more Oct-1 protein than do fetal extracts. The other two bands were more intense in fetal extracts than in adult extracts, but were not supershifted by either Oct-1 or Oct-2 antibodies. Mutation of the silencer response element, mutation of the GC box, and Oct-1 over expression in COS 1 cells increased TR β1 promoter function as assayed by Luciferase reporter. Mutation of the octamer binding site, to which only Oct-1 bound in COS 1 cells, decreased Luciferase reporter activity. Thus the TR β1 promoter was regulated negatively by the proteins bound to the silencer sequence and the GC box, and positively by Oct-1. Silencer and GC box binding proteins are more abundant in fetal brain, and Oct-1 is more abundant in adult brain. The results may be responsible for increased amounts of TR β1 present in late fetal and adult brain.

Thyroid Hormone Receptor β1 Expression in Developing Mouse Limbs and Face.

Thyroid hormone, acting through thyroid hormone receptors (TRs), plays an important role in amphibian metamorphosis and vertebrate development. To identify where and when TR beta 1 promoter is activated during fetal life, we carried out an in vivo functional study of a 1.3 kilobase (kb) TR beta 1 gene promoter using transgenic mice that express the beta-galactosidase gene under control of the TR beta 1 promoter. Transactivation of the gene was determined by blue staining of tissues after incubation with X-gal. High expression of transgene was detected in the limbs and face of the 12.5-day-old fetus (12.5 F) and 14.5 F, reminiscent of the changes occurring during amphibian metamorphosis, and this disappeared at 17.5 F. The expression was confined to the tip of finger bones, between fingers in the limb buds, and was detected in the root of whisker follicles, nose, and around the eyes. Signal was detected in the oral cavity, nasal cavity, lung, and urogenital sinus of 14.5 F, and disappeared at 17.5 F. Signal was detected in the midbrain and auditory vesicles of 9.5 F but was reduced between 12.5F and 17.5F, and there was no expression in the cerebral cortex layer of 0 days old neonates (PO). Expression was detected in the cortex after P5. There was signal in the cerebral cortex, cerebellum, kidney, and liver of adult mice. TR beta 1 messenger RNA was detected by RT-PCR in the developing limbs and face. Transgene expression in the interdigital tissues, which regress during development, suggests that TR beta 1 is expressed in mammals in areas undergoing apoptosis as well as in areas undergoing differentiation.