scholarly journals Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone

2018 ◽  
Vol 19 (10) ◽  
pp. 3284 ◽  
Author(s):  
Brijesh Kumar Singh ◽  
Rohit Anthony Sinha ◽  
Paul Michael Yen
Keyword(s):  
Transcription Factors ◽  
Thyroid Hormone ◽  
Target Genes ◽  
Regulation Of Transcription ◽  
Post Translational Modification ◽  
Hormone Response Elements ◽  
Conventional View ◽  
Metabolic Genes ◽  
Activation Of Transcription ◽  
Rna Transcript

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH.

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.

The Regulation of Target Genes by Co-occupancy of Transcription Factors, c-Myc and Mxi1 with Max in the Mouse Cell Line

2020 ◽  
Vol 15 (6) ◽  
pp. 581-588
Author(s):  
Hui Wang ◽  
Yuan Liu ◽  
Hua Guan ◽  
Guo-Liang Fan
Keyword(s):  
Transcription Factors ◽  
Cancer Cells ◽  
Target Genes ◽  
Gene Expression Regulation ◽  
Regulatory Region ◽  
Mouse Cell ◽  
Regulatory Function ◽  
Regulation Of Transcription ◽  
Specific Regulation ◽  
Synergistic Relationship

Background: The regulatory function of transcription factors on genes is not only related to the location of binding genes and its related functions, but is also related to the methods of binding. Objective: It is necessary to study the regulation effects in different binding methods on target genes. Methods: In this study, we provided a reliable theoretical basis for studying gene expression regulation of co-binding transcription factors and further revealed the specific regulation of transcription factor co-binding in cancer cells. Results: Transcription factors tend to combine with other transcription factors in the regulatory region to form a competitive or synergistic relationship to regulate target genes accurately. Conclusion: We found that up-regulated genes in cancer cells were involved in the regulation of their own immune system related to the normal cells.

scholarly journals The Rat Thyroid Hormone Receptor (TR) Δβ3 Displays Cell-, TR Isoform-, and Thyroid Hormone Response Element-Specific Actions

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1764-1773 ◽  
Author(s):  
Clare B. Harvey ◽  
J. H. Duncan Bassett ◽  
Padma Maruvada ◽  
Paul M. Yen ◽  
Graham R. Williams
Keyword(s):  
Thyroid Hormone ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Cell Types ◽  
Binding Activity ◽  
Hormone Response ◽  
Hormone Response Elements ◽  
Hormone Response Element ◽  
Single Transcript ◽  
Rat Thyroid

The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRβ1 and TRβ2 and two additional variants, TRβ3 and TRΔβ3, of unknown physiological significance. TRβ1, TRβ2, and TRβ3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRΔβ3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRΔβ3 can be translated from a specific TRΔβ3 mRNA or is coexpressed with TRβ3 from a single transcript that contains an internal TRΔβ3 translation start site. In these studies, we provide evidence that the TRβ3/Δβ3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRβ3 with other TR isoforms and investigated mechanisms of action of TRΔβ3 at specific thyroid hormone response elements (TREs) in two cell types. TRβ3 was the most potent isoform, but TR potency was TRE dependent. TRΔβ3 acted as a cell-specific and TRE-dependent modulator of TRβ3 when coexpressed at low concentrations. At higher concentrations, TRΔβ3 was a TRE-selective and cell-specific antagonist of TRα1, -β1, and -β3. Both TRβ3 and TRΔβ3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRΔβ3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action.

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 A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins.

1992 ◽  
Vol 12 (12) ◽  
pp. 5508-5515 ◽  
Author(s):  
T Oehler ◽  
P Angel
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Serum Response Factor ◽  
Limiting Factor ◽  
Regulation Of Transcription ◽  
Physical Interaction ◽  
Main Component

The ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.

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 A developmental stage-specific network approach for studying dynamic co-regulation of transcription factors and microRNAs during craniofacial development

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev192948
Author(s):  
Fangfang Yan ◽  
Peilin Jia ◽  
Hiroki Yoshioka ◽  
Akiko Suzuki ◽  
Junichi Iwata ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Developmental Stage ◽  
Target Genes ◽  
Hippo Pathway ◽  
Craniofacial Development ◽  
Signaling Cascades ◽  
Regulation Of Transcription ◽  
Dependent Manner ◽  
Network Approach

ABSTRACTCraniofacial development is regulated through dynamic and complex mechanisms that involve various signaling cascades and gene regulations. Disruption of such regulations can result in craniofacial birth defects. Here, we propose the first developmental stage-specific network approach by integrating two crucial regulators, transcription factors (TFs) and microRNAs (miRNAs), to study their co-regulation during craniofacial development. Specifically, we used TFs, miRNAs and non-TF genes to form feed-forward loops (FFLs) using genomic data covering mouse embryonic days E10.5 to E14.5. We identified key novel regulators (TFs Foxm1, Hif1a, Zbtb16, Myog, Myod1 and Tcf7, and miRNAs miR-340-5p and miR-129-5p) and target genes (Col1a1, Sgms2 and Slc8a3) expression of which changed in a developmental stage-dependent manner. We found that the Wnt-FoxO-Hippo pathway (from E10.5 to E11.5), tissue remodeling (from E12.5 to E13.5) and miR-129-5p-mediated Col1a1 regulation (from E10.5 to E14.5) might play crucial roles in craniofacial development. Enrichment analyses further suggested their functions. Our experiments validated the regulatory roles of miR-340-5p and Foxm1 in the Wnt-FoxO-Hippo subnetwork, as well as the role of miR-129-5p in the miR-129-5p–Col1a1 subnetwork. Thus, our study helps understand the comprehensive regulatory mechanisms for craniofacial development.

scholarly journals Thyroid Hormone-Regulated Target Genes Have Distinct Patterns of Coactivator Recruitment and Histone Acetylation

2006 ◽  
Vol 20 (3) ◽  
pp. 483-490 ◽  
Author(s):  
Ying Liu ◽  
Xianmin Xia ◽  
Joseph D. Fondell ◽  
Paul M. Yen
Keyword(s):  
Thyroid Hormone ◽  
Histone Acetylation ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Target Genes ◽  
Hormone Response ◽  
Rna Pol Ii ◽  
Pol Ii ◽  
Response Elements ◽  
Hormone Response Elements ◽  
Endogenous Target

Abstract Thyroid hormone receptors (TRs) are ligand-regulated transcription factors that bind to thyroid hormone response elements of target genes. Upon ligand binding, they recruit coactivator complexes that increase histone acetylation and recruit RNA polymerase II (Pol II) to activate transcription. Recent studies suggest that nuclear receptors and coactivators may have temporal recruitment patterns on hormone response elements, yet little is known about the nature of the patterns at multiple endogenous target genes. We thus performed chromatin immunoprecipitation assays to investigate coactivator recruitment and histone acetylation patterns on the thyroid hormone response elements of four endogenous target genes (GH, sarcoplasmic endoplasmic reticulum calcium-adenosine triphosphatase, phosphoenolpyruvate carboxykinase, and cholesterol 7α-hydroxylase) in a rat pituitary cell line that expresses TRs. We found that TRβ, several associated coactivators (steroid receptor coactivator-1, glucocorticoid receptor interacting protein-1, and TR-associated protein 220), and RNA Pol II were rapidly recruited to thyroid hormone response elements as early as 15 min after T3 addition. When the four target genes were compared, we observed differences in the types and temporal patterns of recruited coactivators and histone acetylation. Interestingly, the temporal pattern of RNA Pol II was similar for three genes studied. Our findings suggest that thyroid hormone-regulated target genes may have distinct patterns of coactivator recruitment and histone acetylation that may enable highly specific regulation.

A common intermediary factor (p52/54) recognizing "acidic blob"-type domains is required for transcriptional activation by the Jun proteins

1992 ◽  
Vol 12 (12) ◽  
pp. 5508-5515
Author(s):  
T Oehler ◽  
P Angel
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Serum Response Factor ◽  
Limiting Factor ◽  
Regulation Of Transcription ◽  
Physical Interaction ◽  
Main Component

The ability of the c-Jun protein, the main component of the transcription factor AP1, to interact directly or indirectly with the RNA polymerase II-initiation complex to activate transcription was investigated by in vivo transcription interference ("squelching") experiments. Coexpression of a Jun mutant lacking its DNA binding domain strongly represses the activity of wild-type c-Jun. Repression depends on the presence of the transactivation domains (TADs), suggesting that a limiting factor interacting with the TADs is essential to link Jun and the components of the transcriptional machinery. The activity of this intermediary factor(s) is restricted to TADs characterized by an abundance of negatively charged amino acids, as demonstrated by the abilities of the TADs of JunB, GAL4, and VP16 to repress c-Jun activity. Depending on the presence of the TADs of Jun, we found physical interaction between Jun and a cluster of three proteins with molecular masses of 52, 53, and 54 kDa (p52/54). Association between Jun and p52/54 is strongly reduced in the presence of VP16, suggesting that the two proteins compete for binding to p52/54. Transcription factors containing a different type of TAD (e.g., GHF1, estrogen receptor, or serum response factor) fail to inhibit Jun activity, suggesting that these proteins act through a different mechanism. We consider the requirement of Jun to interact with p52/54 utilized by other transcription factors a new mechanism in the regulation of transcription of Jun-dependent target genes.

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