scholarly journals Physiologic Significance of Epigenetic Regulation of Thyroid Hormone Target Gene Expression

2020 ◽  
Vol 9 (3) ◽  
pp. 114-123
Author(s):  
João Anselmo ◽  
Carolina M. Chaves
Keyword(s):  
Thyroid Hormone ◽  
Epigenetic Regulation ◽  
Target Genes ◽  
Epigenetic Inheritance ◽  
Thyroid Stimulating Hormone ◽  
Epigenetic Mechanism ◽  
Gene Encoding ◽  
Epigenetic Effect ◽  
Type 3

Background: In previous publications, we have reported our findings demonstrating that exposure to high maternal levels of thyroid hormones (TH) has life-long effects on the wild-type (WT, without THRB mutation) progeny of mothers with resistance to thyroid hormone beta (RTHβ). The mechanism of this epigenetic effect remains unclear. Objectives: We reviewed the mechanisms involved in the epigenetic regulation of TH target genes and understand how they may explain the reduced sensitivity to TH in the WT progeny of RTHβ mothers. Methods: The availability of a large, formerly genotyped Azorean population with many individuals harboring the THRB mutation, R243Q, provided us a model to study the influence of fetal exposure to high maternal TH levels. Results: The thyroid-stimulating hormone (TSH) response in WT adults was less suppressible following the administration of L-triiodothyronine (L-T3). This finding suggests reduced sensitivity to TH that is induced by an epigenetic mechanism resulting from exposure to high maternal levels of TH during pregnancy. The persistence of this effect across 3 generations of WT subjects favors transgenerational epigenetic inheritance. Based on preliminary studies in mice, we identified the naturally imprinted gene encoding deiodinase type 3, i.e., DIO3, as a possible mediator of this epigenetic effect through increased inactivation of TH. Conclusion: Increased D3 expression and consequently increased T3 degradation appear to be responsible for the reduced sensitivity of the anterior pituitary to administered L-T3. The imprinted DIO3 gene may be a candidate gene that mediates the epigenetic effect induced by exposure to high maternal levels of TH. However, we cannot exclude the role of other TH-responsive genes.

Neutralization of TNF does not influence endotoxininduced changes in thyroid hormone metabolism in humans

1999 ◽  
Vol 276 (2) ◽  
pp. R357-R362 ◽  
Author(s):  
Tom van der Poll ◽  
Erik Endert ◽  
Susette M. Coyle ◽  
Jan M. Agosti ◽  
Stephen F. Lowry
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Stimulating Hormone ◽  
Hormone Metabolism ◽  
Thyroid Hormone Metabolism ◽  
Healthy Humans ◽  
Transient Rise ◽  
Induced Changes ◽  
Necrosis Factor ◽  
Control Study

To determine the role of tumor necrosis factor (TNF) in endotoxin-induced changes in plasma thyroid hormone and thyroid-stimulating hormone (TSH) concentrations, 24 healthy postabsorptive humans were studied on a control study day ( n= 6), after infusion of a recombinant TNF receptor IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) after intravenous injection of endotoxin (2 ng/kg; n = 6), or after administration of endotoxin with TNFR:Fc ( n = 6). Administration of TNFR:Fc alone did not affect thyroid hormone or TSH levels when compared with the control day. Endotoxin induced a transient rise in plasma TNF activity (1.5 h: 219 ± 42 pg/ml), which was completely prevented by TNFR:Fc ( P < 0.05). After endotoxin administration, plasmal-thyroxine (T4), free T4, 3,5,3′-triiodothyronine (T3), and TSH were lower and 3,3′,5′-triiodothyronine was higher than on the control day (all P < 0.05). Coinfusion of TNFR:Fc with endotoxin did not influence these endotoxin-induced changes. Our results suggest that endogenous TNF does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

scholarly journals Transgenic Analysis Reveals that Thyroid Hormone Receptor Is Sufficient To Mediate the Thyroid Hormone Signal in Frog Metamorphosis

2004 ◽  
Vol 24 (20) ◽  
pp. 9026-9037 ◽  
Author(s):  
Daniel R. Buchholz ◽  
Akihiro Tomita ◽  
Liezhen Fu ◽  
Bindu D. Paul ◽  
Yun-Bo Shi
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Gene Activation ◽  
Inducible Promoter ◽  
Vertebrate Development ◽  
Transcription System

ABSTRACT Thyroid hormone (T3) has long been known to be important for vertebrate development and adult organ function. Whereas thyroid hormone receptor (TR) knockout and transgenic studies of mice have implicated TR involvement in mammalian development, the underlying molecular bases for the resulting phenotypes remain to be determined in vivo, especially considering that T3 is known to have both genomic, i.e., through TRs, and nongenomic effects on cells. Amphibian metamorphosis is an excellent model for studying the role of TR in vertebrate development because of its total dependence on T3. Here we investigated the role of TR in metamorphosis by developing a dominant positive mutant thyroid hormone receptor (dpTR). In the frog oocyte transcription system, dpTR bound a T3-responsive promoter and activated the promoter independently of T3. Transgenic expression of dpTR under the control of a heat shock-inducible promoter in premetamorphic tadpoles led to precocious metamorphic transformations. Molecular analyses showed that dpTR induced metamorphosis by specifically binding to known T3 target genes, leading to increased local histone acetylation and gene activation, similar to T3-bound TR during natural metamorphosis. Our experiments indicated that the metamorphic role of T3 is through genomic action of the hormone, at least on the developmental parameters tested. They further provide the first example where TR is shown to mediate directly and sufficiently these developmental effects of T3 in individual organs by regulating target gene expression in these organs.

scholarly journals Spermatogonial Type 3 Deiodinase Regulates Thyroid Hormone Target Genes in Developing Testicular Somatic Cells

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2929-2945
Author(s):  
M Elena Martinez ◽  
Christine W Lary ◽  
Aldona A Karaczyn ◽  
Michael D Griswold ◽  
Arturo Hernandez
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Genes ◽  
Somatic Cells ◽  
Published Data ◽  
Data Sets ◽  
Testicular Cells ◽  
Differentiation And Proliferation ◽  
Neonatal Testis ◽  
Type 3

Abstract Premature overexposure to thyroid hormone causes profound effects on testis growth, spermatogenesis, and male fertility. We used genetic mouse models of type 3 deiodinase (DIO3) deficiency to determine the genetic programs affected by premature thyroid hormone action and to define the role of DIO3 in regulating thyroid hormone economy in testicular cells. Gene expression profiling in the neonatal testis of DIO3-deficient mice identified 5699 differentially expressed genes. Upregulated and downregulated genes were, respectively, involved according to DAVID analysis with cell differentiation and proliferation. They included anti-Müllerian hormone and genes involved in the formation of the blood–testis barrier, which are specific to Sertoli cells (SCs). They also included steroidogenic genes, which are specific to Leydig cells. Comparison with published data sets of genes enriched in SCs and spermatogonia, and responsive to retinoic acid (RA), identified a subset of genes that were regulated similarly by RA and thyroid hormone. This subset of genes showed an expression bias, as they were downregulated when enriched in spermatogonia and upregulated when enriched in SCs. Furthermore, using a genetic approach, we found that DIO3 is not expressed in SCs, but spermatogonia-specific inactivation of DIO3 led to impaired testis growth, reduced SC number, decreased cell proliferation and, especially during neonatal development, altered gene expression specific to somatic cells. These findings indicate that spermatogonial DIO3 protects testicular cells from untimely thyroid hormone signaling and demonstrate a mechanism of cross-talk between somatic and germ cells in the neonatal testis that involves the regulation of thyroid hormone availability and action.

Role of thyroglobulin endocytic pathways in the control of thyroid hormone release

2000 ◽  
Vol 279 (5) ◽  
pp. C1295-C1306 ◽  
Author(s):  
Michele Marinò ◽  
Robert T. McCluskey
Keyword(s):  
Thyroid Hormone ◽  
Intracellular Trafficking ◽  
Fluid Phase ◽  
Thyroid Stimulating Hormone ◽  
Asialoglycoprotein Receptor ◽  
Hormone Release ◽  
Hormone Stimulation ◽  
High Affinity ◽  
Endocytic Pathways

Thyroglobulin (Tg), the thyroid hormone precursor, is synthesized by thyrocytes and secreted into the colloid. Hormone release requires uptake of Tg by thyrocytes and degradation in lysosomes. This process must be precisely regulated. Tg uptake occurs mainly by micropinocytosis, which can result from both fluid-phase pinocytosis and receptor-mediated endocytosis. Because Tg is highly concentrated in the colloid, fluid-phase pinocytosis or low-affinity receptors should provide sufficient Tg uptake for hormone release; high-affinity receptors may serve to target Tg away from lysosomes, through recycling into the colloid or by transcytosis into the bloodstream. Several apical receptors have been suggested to play roles in Tg uptake and intracellular trafficking. A thyroid asialoglycoprotein receptor may internalize and recycle immature forms of Tg back to the colloid, a function also attributed to an as yet unidentified N-acetylglucosamine receptor. Megalin mediates Tg uptake by thyrocytes, especially under intense thyroid-stimulating hormone stimulation, resulting in transcytosis of Tg from the colloid to the bloodstream, a function that prevents excessive hormone release.

scholarly journals Critical Role of Types 2 and 3 Deiodinases in the Negative Regulation of Gene Expression by T3 in the Mouse Cerebral Cortex

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2919-2928 ◽  
Author(s):  
Arturo Hernandez ◽  
Beatriz Morte ◽  
Mónica M. Belinchón ◽  
Ainhoa Ceballos ◽  
Juan Bernal
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Thyroid Hormone ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Control Of Gene Expression ◽  
High Doses ◽  
And Function ◽  
Type 3

Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T3 to nuclear receptors. Brain T3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T4 and T3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels.

Effect of thyroid hormone on myocardial catecholamine content of the guinea pig

1961 ◽  
Vol 201 (6) ◽  
pp. 1049-1052 ◽  
Author(s):  
M. Jay Goodkind ◽  
David H. Fram ◽  
Michael Roberts
Keyword(s):  
Thyroid Hormone ◽  
Guinea Pig ◽  
Thyroid Function ◽  
Serum Protein ◽  
Guinea Pigs ◽  
Thyroid Stimulating Hormone ◽  
Catecholamine Content ◽  
Norepinephrine Content ◽  
Stimulating Hormone

Normal and thyroidectomized guinea pigs were subjected to treatment with either triiodothyronine or thyroid-stimulating hormone. Determinations of myocardial catecholamine content and serum protein-bound iodine revealed a significant increase in myocardial norepinephrine content in the markedly thyrotoxic animal, and a significant decrease in norepinephrine content of the myocardium of hypothyroid animals. The significance of these findings in defining the role of catecholamines in various states of thyroid function is discussed.

Regulation of the uncoupling protein gene expression

1997 ◽  
Vol 136 (3) ◽  
pp. 251-264 ◽  
Author(s):  
J Enrique Silva ◽  
Rogerio Rabelo
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Uncoupling Protein ◽  
Regulatory Element ◽  
Gene Encoding ◽  
Response Elements ◽  
Brown Adipose ◽  
A Cell

Abstract Uncoupling protein (UCP) is essential to the thermogenic function of brown adipose tissue (BAT). The thermogenic role of this protein is due to its capacity to uncouple oxidative phosphorylation in a regulated manner. The thermogenic potential of BAT is determined by its content of UCP. The gene encoding this protein is under complex regulation. Catecholamines, via cAMP, thyroid hormone and retinoic acid, directly stimulate the gene acting upon an upstream (−2·28/−2·49 kb) enhancer sequence, but cAMP may act upon other sequences of the gene as well. CCAAT enhancer binding proteins and peroxisome proliferation activator receptor (PPAR)γ2 have also been implicated in the regulation of the gene acting on discrete sequences. While the thyroid hormone response and retinoic acid response elements (TRE and RARE) have been well defined, the cAMP response elements (CRE) remain elusive. The two TREs are 27 bp apart between −2·33 kb and −2·39 kb. The synergism between cAMP and thyroid hormone seems to reside in a 39 bp sequence downstream (−2·28/−2·32 kb). The most important CRE, the RARE, a cell-specific enhancer and a putative PPAR element are all concentrated in a 90 bp regulatory element of great complexity (−2·40/−22·49 kb). Other hormones, such as insulin and glucocorticoids, and IGF-I also modulate the expression of the gene but their effects seem to be largely indirect. Understanding the regulation of the UCP gene expression may facilitate the development of interventions in obesity and related disorders. European Journal of Endocrinology 136 251–264

scholarly journals Regulation of type 3 deiodinase in rodent liver and adipose tissue during fasting

2020 ◽  
Vol 9 (6) ◽  
pp. 552-562
Author(s):  
Emmely M de Vries ◽  
Hermina C van Beeren ◽  
Albert C W A van Wijk ◽  
Andries Kalsbeek ◽  
Johannes A Romijn ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Mrna Expression ◽  
Constitutive Androstane Receptor ◽  
Mtor Inhibitors ◽  
Rat Hepatocytes ◽  
Primary Hepatocytes ◽  
Type 3 ◽  
Stimulation Of

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four-hour fasting increased liver Dio3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced Dio3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both Dio3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, Dio3 mRNA expression increased five-fold after 48-h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced Dio3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce Dio3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Cognitive and Behavioral Complications of Congenital Hypothyroidism

2010 ◽  
Author(s):  
Ruth D. Nass
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Brain Development ◽  
Congenital Hypothyroidism ◽  
Behavioral Problems ◽  
Thyroid Stimulating Hormone ◽  
Primary Hypothyroidism ◽  
Normal Brain ◽  
Gene Encoding ◽  
Hormone Synthesis

Congenital hypothyroidism (CH) affects approximately 1 in 3,500 newborns. There is a female preponderance. In areas of iodine insufficiency, the incidence is higher, since iodine is a key element in the synthesis of thyroid hormone. Approximately 85% of CH cases are sporadic, whereas 15% are hereditary. Thyroid hormone is essential for normal pre- and postnatal brain development. The importance of in utero thyroid hormone status is demonstrated by the fact that maternal hypothyroidism during pregnancy is known to result in cognitive and motor deficits in the offspring (Forrest 2004; Zoeller and Rovet 2004). Congenital hypothyroidism is already expressed in fetal life; maternal T4, transferred via the placenta, is not sufficient for normal brain development (Forrest 2004; Haddow et al. 1999; Opazo et al. 2008; Pop and Vulsma 2005). Prior to newborn screening, CH that went undiagnosed and untreated for more than 3 months was associated with permanent and significant mental retardation, as well as behavioral problems. Outcome is now significantly better. Children with CH have normal intelligence, although subtle and specific cognitive and behavioral problems occur. Congenital hypothyroidism can be caused by primary hypothyroidism, due to a defect of the thyroid gland, or by central hypothyroidism secondary to defective hypothalamic or pituitary regulation of thyroid hormone. Several types of primary thyroid abnormalities may occur. Thyroid dysgenesis is the result of a missing, ectopic, or hypoplastic gland. Proteins that are crucial for normal thyroid gland development include the thyroid transcription factors PAX8, TTF1, TTF2, FOXE1 and the thyroid stimulating hormone (TSH) receptor gene. Thyroid dyshormonogenesis is generally due to an autosomal recessive genetic defect in any of many stages of thyroid hormone synthesis, secretion and transport (Moreno and Visser 2007). One in 50,000 children has autosomal dominant thyroid hormone resistance (RTH) due to a mutation in the gene encoding for the TRb thyroid receptors (Hauser et al. 1993; Weiss et al. 1993). Iodine deficiency can also cause CH (endemic cretinism) (DeLange et al. 2000). Gaudino and colleagues (2005) determined the etiology of CH in 49 non-athyroid cases.

scholarly journals Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

2017 ◽  
Vol 114 (52) ◽  
pp. E11323-E11332 ◽  
Author(s):  
G. Sebastian Hönes ◽  
Helena Rakov ◽  
John Logan ◽  
Xiao-Hui Liao ◽  
Eugenie Werbenko ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Dna Binding ◽  
Target Genes ◽  
Skeletal Development ◽  
Nuclear Signaling ◽  
Physiological Relevance ◽  
Pituitary Thyroid Axis ◽  
Second Messenger Signaling ◽  
Type 3

Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.

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