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.

scholarly journals The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis

Endocrinology ◽  
2016 ◽  
Vol 157 (3) ◽  
pp. 1276-1288 ◽  
Author(s):  
M. Elena Martinez ◽  
Aldona Karaczyn ◽  
J. Patrizia Stohn ◽  
William T. Donnelly ◽  
Walburga Croteau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Critical Factor ◽  
Monocarboxylate Transporter ◽  
Seminiferous Tubules ◽  
Testis Size ◽  
Critical Determinant ◽  
Testis Development ◽  
Neonatal Testis ◽  
Type 3

Abstract Timely and appropriate levels of thyroid hormone (TH) signaling are necessary to ensure normal developmental outcomes in many tissues. Studies using pharmacological models of altered TH status have revealed an influence of these hormones on testis development and size, but little is known about the role of endogenous determinants of TH action in the developing male gonads. Using a genetic approach, we demonstrate that the type 3 deiodinase (D3), which inactivates TH and protects developing tissues from undue TH action, is a key factor. D3 is highly expressed in the developing testis, and D3-deficient (D3KO) mice exhibit thyrotoxicosis and cell proliferation arrest in the neonatal testis, resulting in an approximately 75% reduction in testis size. This is accompanied by larger seminiferous tubules, impaired spermatogenesis, and a hormonal profile indicative of primary hypogonadism. A deficiency in the TH receptor-α fully normalizes testis size and adult testis gene expression in D3KO mice, indicating that the effects of D3 deficiency are mediated through this type of receptor. Similarly, genetic deficiencies in the D2 or in the monocarboxylate transporter 8 partially rescue the abnormalities in testis size and gonadal axis gene expression featured in the D3KO mice. Our study highlights the testis as an important tissue in which determinants of TH action coordinately converge to ensure normal development and identifies D3 as a critical factor in testis development and in testicular protection from thyrotoxicosis.

scholarly journals Carbohydrate Response Element Binding Protein Gene Expression Is Positively Regulated by Thyroid Hormone

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3417-3424 ◽  
Author(s):  
Koshi Hashimoto ◽  
Emi Ishida ◽  
Shunichi Matsumoto ◽  
Shuichi Okada ◽  
Masanobu Yamada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Target Genes ◽  
Binding Protein ◽  
Gene Promoter ◽  
Direct Repeat ◽  
Transcriptional Level ◽  
Hepatic Lipogenesis ◽  
Response Element ◽  
Element Binding Protein

The molecular mechanism of thyroid hormone (TH) effects to fatty acid metabolism in liver is yet to be clear. The carbohydrate response element-binding protein (ChREBP) as well as sterol response element-binding protein (SREBP)-1c plays a pivotal role in hepatic lipogenesis. Both SREBP-1c and ChREBP are target genes of liver X receptors (LXRs). Because LXRs and TH receptors (TRs) cross talk mutually in many aspects of transcription, we examined whether TRs regulate the mouse ChREBP gene expression. In the current study, we demonstrated that TH up-regulated mouse ChREBP mRNA and protein expression in liver. Run-on and luciferase assays showed that TH and TR-β1 positively regulated the ChREBP gene transcription. The mouse ChREBP gene promoter contains two direct repeat-4 sites (LXRE1 and LXRE2) and EMSAs demonstrated that LXR-α and TR-β1 prefer to bind LXRE1 and LXRE2, respectively. The direct repeat-4 deletion and LXRE2 mutants of the promoter deteriorate the positive regulation by TR-β1, indicating that LXRE2 is functionally important for the regulation. We also showed that human ChREBP gene expression and promoter activities were up-regulated by TH. These data suggest that ChREBP mRNA expression is positively regulated by TR-β1 and TH at the transcriptional level in mammals. This novel observation indicates that TH fine-tunes hepatic lipogenesis via regulating SREBP-1c and ChREBP gene expression reciprocally.

The dominant negative thyroid hormone receptor β-mutant Δ337T alters PPARα signaling in heart

2007 ◽  
Vol 292 (2) ◽  
pp. E453-E460 ◽  
Author(s):  
Norman E. Buroker ◽  
Martin E. Young ◽  
Caimiao Wei ◽  
Kyle Serikawa ◽  
Ming Ge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Protein Content ◽  
Nuclear Receptors ◽  
Cross Talk ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Dominant Negative ◽  
Variable Cross ◽  
Multiple Genes

PPARα and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPARα regulation of target genes and used mice exhibiting a cardioselective Δ337T TRβ1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TRα and TRβ. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic (MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPARα ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPARα, TRα2, RXRβ, or PGC-1α. However, protein content for TRα1 and the PPARα heterodimeric partner RXRα was diminished in MUT, whereas PPARβ increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The non-ligand-binding TRβ1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPARα ligands may be determined by thyroid hormone state and TR function.

scholarly journals Thyroid Hormone-Dependent Gene Expression in Differentiated Embryonic Stem Cells and Embryonal Carcinoma Cells: Identification of Novel Thyroid Hormone Target Genes by Deoxyribonucleic Acid Microarray Analysis

Endocrinology ◽  
2005 ◽  
Vol 146 (2) ◽  
pp. 776-783 ◽  
Author(s):  
Yan-Yun Liu ◽  
Gregory A. Brent
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Thyroid Hormone ◽  
Early Development ◽  
Target Genes ◽  
Es Cells ◽  
Embryonic Stem ◽  
Wild Type ◽  
Ec Cells

Abstract T3 is required for normal early development, but relatively few T3-responsive target genes have been identified. In general, in vitro stem cell differentiation techniques stimulate a wide range of developmental programs, including thyroid hormone receptor (TR) pathways. We developed several in vitro stem cell models to more specifically identify TR-mediated gene expression in early development. We found that embryonic carcinoma (EC) cells have reduced T3 nuclear binding capacity and only modestly express the known T3 target genes, neurogranin (RC3) and Ca2+/calmodulin-dependent protein kinase IV (CaMKIV), in response to T3. Full T3 induction in transient transfection of EC cells was restored with cotransfection of a TR expression vector. We, therefore, performed gene expression profiles in wild-type embryonic stem (ES) cells compared with expression in cells with deficient (EC) or mutant TR (TRα P398H mutant ES cells), to identify T3 target genes. T3 stimulation of wild-type ES cells altered mRNA expression of 610 known genes (26% of those studied), although only approximately 60 genes (1%) met criteria for direct T3 stimulation based on the magnitude of induction and requirement for the presence of TR. We selected five candidate T3 target genes, neurexophilin 2, spermatid perinuclear RNA-binding protein (SPNR), kallikrein-binding protein (KBP), prostate-specific membrane antigen (PSMA), and synaptotagmin II, for more detailed study. T3 responsiveness of these genes was evaluated in both in vitro endogenous gene expression and in vivo mouse model systems. These genes identified in a novel stem cell system, including those induced and repressed in response to T3, may mediate thyroid hormone actions in early development.

Estrogen-Regulated Genes Predict Survival in Hormone Receptor–Positive Breast Cancers

2006 ◽  
Vol 24 (11) ◽  
pp. 1656-1664 ◽  
Author(s):  
Daniel S. Oh ◽  
Melissa A. Troester ◽  
Jerry Usary ◽  
Zhiyuan Hu ◽  
Xiaping He ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Published Data ◽  
Data Sets ◽  
Breast Cancers ◽  
Outcome Predictor ◽  
Training Set ◽  
Hormone Receptor Positive ◽  
Prognosis Group ◽  
Mcf 7

Purpose The prognosis of a patient with estrogen receptor (ER) and/or progesterone receptor (PR) –positive breast cancer can be highly variable. Therefore, we developed a gene expression–based outcome predictor for ER+ and/or PR+ (ie, luminal) breast cancer patients using biologic differences among these tumors. Materials and Methods The ER+ MCF-7 breast cancer cell line was treated with 17β-estradiol to identify estrogen-regulated genes. These genes were used to develop an outcome predictor on a training set of 65 luminal epithelial primary breast carcinomas. The outcome predictor was then validated on three independent published data sets. Results The estrogen-induced gene set identified in MCF-7 cells was used to hierarchically cluster a 65 tumor training set into two groups, which showed significant differences in survival (P = .0004). Supervised analyses identified 822 genes that optimally defined these two groups, with the poor-prognosis group IIE showing high expression of cell proliferation and antiapoptosis genes. The good prognosis group IE showed high expression of estrogen- and GATA3-regulated genes. Mean expression profiles (ie, centroids) created for each group were applied to ER+ and/or PR+ tumors from three published data sets. For all data sets, Kaplan-Meier survival analyses showed significant differences in relapse-free and overall survival between group IE and IIE tumors. Multivariate Cox analysis of the largest test data set showed that this predictor added significant prognostic information independent of standard clinical predictors and other gene expression–based predictors. Conclusion This study provides new biologic information concerning differences within hormone receptor–positive breast cancers and a means of predicting long-term outcomes in tamoxifen-treated patients.

scholarly journals Novel Mechanism of Positive versus Negative Regulation by Thyroid Hormone Receptor β1 (TRβ1) Identified by Genome-wide Profiling of Binding Sites in Mouse Liver

2013 ◽  
Vol 289 (3) ◽  
pp. 1313-1328 ◽  
Author(s):  
Preeti Ramadoss ◽  
Brian J. Abraham ◽  
Linus Tsai ◽  
Yiming Zhou ◽  
Ricardo H. Costa-e-Sousa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Thyroid Hormone ◽  
Binding Sites ◽  
Hormone Receptor ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Negative Regulation ◽  
Genome Wide

Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRβ1. However, the number of known target genes directly regulated by TRβ1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRβ1 cistrome in vivo, we expressed a biotinylated TRβ1 in hypo- and hyperthyroid mouse livers, used ChIP-seq to identify genomic TRβ1 targets, and correlated these data with gene expression changes. As with other nuclear receptors, the majority of TRβ1 binding sites were not in proximal promoters but in the gene body of known genes. Remarkably, T3 can dictate changes in TRβ1 binding, with strong correlation to T3-induced gene expression changes, suggesting that differential TRβ1 binding regulates transcriptional outcome. Additionally, DR-4 and DR-0 motifs were significantly enriched at binding sites where T3 induced an increase or decrease in TRβ1 binding, respectively, leading to either positive or negative regulation by T3. Taken together, the results of this study provide new insights into the mechanisms of transcriptional regulation by TRβ1 in vivo.

scholarly journals Expresso: A database and web server for exploring the interaction of transcription factors and their target genes in Arabidopsis thaliana using ChIP-Seq peak data

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 372 ◽  
Author(s):  
Delasa Aghamirzaie ◽  
Karthik Raja Velmurugan ◽  
Shuchi Wu ◽  
Doaa Altarawy ◽  
Lenwood S. Heath ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Data Sets ◽  
Motif Analysis ◽  
Chromatin Immunoprecipitation Sequencing

Motivation: The increasing availability of chromatin immunoprecipitation sequencing (ChIP-Seq) data enables us to learn more about the action of transcription factors in the regulation of gene expression. Even though in vivo transcriptional regulation often involves the concerted action of more than one transcription factor, the format of each individual ChIP-Seq dataset usually represents the action of a single transcription factor. Therefore, a relational database in which available ChIP-Seq datasets are curated is essential. Results: We present Expresso (database and webserver) as a tool for the collection and integration of available Arabidopsis ChIP-Seq peak data, which in turn can be linked to a user’s gene expression data. Known target genes of transcription factors were identified by motif analysis of publicly available GEO ChIP-Seq data sets. Expresso currently provides three services: 1) Identification of target genes of a given transcription factor; 2) Identification of transcription factors that regulate a gene of interest; 3) Computation of correlation between the gene expression of transcription factors and their target genes. Availability: Expresso is freely available at http://bioinformatics.cs.vt.edu/expresso/

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.

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

Endocrinology ◽  
2018 ◽  
Vol 159 (7) ◽  
pp. 2576-2595 ◽  
Author(s):  
Brenda J Mengeling ◽  
Michael L Goodson ◽  
J David Furlow
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Xenopus Laevis ◽  
Animal Studies ◽  
Time Course ◽  
Hormone Receptors ◽  
Target Genes ◽  
Environmental Pollutant ◽  
Luciferase Reporter ◽  
X Receptors

Abstract 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.

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