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Isoform-specific transcriptional activity of overlapping target genes that respond to thyroid hormone receptors alpha1 and beta1.

ABSTRACT: Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of physiology and development. TRs are expressed in vertebrates as a series of distinct isoforms that exert distinct biological roles. We wished to determine whether the two most widely expressed isoforms, TR alpha 1 and TR beta 1, exert their different biological effects by regulating different sets of target genes. Using stably transformed HepG2 cells and a microarray analysis, we were able to demonstrate that TR alpha 1 and TR beta 1 regulate a largely overlapping repertoire of target genes in response to T(3) hormone. However, these two isoforms display very different transcriptional properties on each individual target gene, ranging from a much greater T(3)-mediated regulation by TR alpha 1 than by TR beta 1, to near equal regulation by both isoforms. We also identified TR alpha 1 and TR beta 1 target genes that were regulated by these receptors in a hormone-independent fashion. We suggest that it is this gene-specific, isoform-specific amplitude of transcriptional regulation that is the likely basis for the appearance and maintenance of TR alpha 1 and TR beta 1 over evolutionary time. In essence, TR alpha 1 and TR beta 1 adjust the magnitude of the transcriptional response at different target genes to different levels; by altering the ratio of these isoforms in different tissues or at different developmental times, the intensity of T(3) response can be individually tailored to different physiological and developmental requirements.

SUBMITTER: Chan IH

PROVIDER: S-EPMC2775939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Isoform-specific transcriptional activity of overlapping targets that respond to thyroid hormone receptors a1 and b1

Project description:Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of physiology and development. TRs are expressed in vertebrates as a series of distinct isoforms that exert distinct biological roles. We wished to determine if the two most widely expressed isoforms, TRa1 and TRb1, exert their different biological effects by regulating different sets of target genes. Using stably transformed HepG2 cells and a microarray analysis, we were able to demonstrate that TRa1 and TRb1 regulate a largely overlapping repertoire of target genes in response to T3 hormone. However, these two isoforms display very different transcriptional properties on each individual target gene, ranging from a much greater T3-mediated regulation by TRa1 than by TRb1, to near equal regulation by both isoforms. We also identified TRa1 and TRb1 target genes that were regulated by these receptors in a hormone-independent fashion. We suggest that it is this gene-specific, isoform-specific amplitude of transcriptional regulation that is the likely basis for the appearance and maintenance of TRa1 and TRb1 over evolutionary time. In essence, TRa1 and TRb1 adjust the magnitude of the transcriptional response at different target genes to different levels; by altering the ratio of these isoforms in different tissues or at different developmental times, the intensity of T3 response can be individually tailored to different physiological and developmental requirements. TRa1, TRb1, or empty plasmid control stably transfected HepG2 cells were treated with 100 nM T3 or with ethanol carrier alone for 6h. Three independent biological repeats were analyzed for each of the three transformant pools (empty plasmid control, TRa1, and TRb1).

2009-08-08 | E-GEOD-17561 | biostudies-arrayexpress

Isoform-specific transcriptional activity of overlapping targets that respond to thyroid hormone receptors a1 and b1

2009-08-08 | GSE17561 | GEO

Thyroid hormone induces cerebellar Purkinje cell dendritic development via the thyroid hormone receptor alpha1.

Project description:The thyroid hormone l-3,3',5-triiodothyronine (T3) plays an important role during cerebellar development. Perinatal T3 deficiency leads to severe cellular perturbations, among them a striking reduction in the growth and branching of Purkinje cell dendritic arborization. The molecular mechanisms underlying these effects are poorly understood. Despite the well documented broad expression of thyroid hormone receptors (TRs), analysis of different TR-deficient mice has failed to provide detailed information about the function of distinct TRs during neuronal development. The cerebellar cell culture systems offer an excellent model by which to study the effects of T3, because differentiation of cerebellar neurons in mixed and purified cultures proceeds in the absence of serum that contains T3. Addition of T3 to cerebellar cultures causes a dramatic increase in Purkinje cell dendrite branching and caliber in a dose- and time-dependent manner. Furthermore, we demonstrate for the first time that T3 acts on Purkinje cells directly through TRalpha1 expressed on the Purkinje cell and not on the granule cell, the presynaptic partner of Purkinje cells. In contrast, TRbeta isoforms are not involved, because Purkinje cells derived from TRbeta-/- mice show the same T3 responsiveness as wild-type cells. T3-promoted Purkinje cell differentiation was not mediated via neurotrophins, as suggested previously, because dendritogenesis of Purkinje cells from BDNF-/- mice could be effectively stimulated in vitro by T3 treatment. Furthermore, the effects of T3 observed were not abolished by tyrosine kinase receptor B (TrkB)-IgG, TrkC-IgG, or K252a, agents known to block the actions of neurotrophin. These results indicate that T3 directly affects Purkinje cell differentiation through activation of the TRalpha1.

| S-EPMC6740935 | biostudies-literature

Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis.

Project description:Thyroid hormone regulates adult hippocampal neurogenesis, a process involved in key functions, such as learning, memory, and mood regulation. We addressed the role of thyroid hormone receptor TRα1 in adult hippocampal neurogenesis, using mice harboring a TRα1 null allele (TRα1(-/-)), overexpressing TRα1 6-fold (TRα2(-/-)), and a mutant TRα1 (TRα1(+/m)) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TRα1(-/-) mice exhibited a significant increase in doublecortin-positive immature neurons and increased survival of bromodeoxyuridine-positive (BrdU(+)) progenitors as compared to wild-type controls. In contrast, the TRα1(+/m) and the TRα2(-/-) mice, where the overexpressed TRα1 acts as an aporeceptor, showed a significant decline in surviving BrdU(+) progenitors. TRα1(-/-) and TRα2(-/-) mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRα2(-/-) and TRα1(+/m) mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRα1(+/m) mice. These mice also exhibited a decrease in NeuroD(+) cell numbers in the dentate gyrus, suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unliganded TRα1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.

| S-EPMC4177098 | biostudies-literature

An Atlas of Thyroid Hormone Receptors' Target Genes in Mouse Tissues.

Project description:We gathered available RNA-seq and ChIP-seq data in a single database to better characterize the target genes of thyroid hormone receptors in several cell types. This database can serve as a resource to analyze the mode of action of thyroid hormone (T3). Additionally, it is an easy-to-use and convenient tool to obtain information on specific genes regarding T3 regulation or to extract large gene lists of interest according to the users' criteria. Overall, this atlas is a unique compilation of recent sequencing data focusing on T3, its receptors, modes of action, targets and roles, which may benefit researchers within the field. A preliminary analysis indicates extensive variations in the repertoire of target genes where transcription is upregulated by chromatin-bound nuclear receptors. Although it has a major influence, chromatin accessibility is not the only parameter that determines the cellular selectivity of the hormonal response.

| S-EPMC9570117 | biostudies-literature

Differential recruitment of nuclear coregulators directs the isoform-dependent action of mutant thyroid hormone receptors.

Project description:Studies using mice deficient in thyroid hormone receptors (TR) indicate that the two TR isoforms, TRα1 and TRβ1, in addition to mediating overlapping biological activities of the thyroid hormone, T3, also mediate distinct functions. Mice harboring an identical dominant negative mutation (denoted PV) at the C terminus of TRα1 (Thra1(PV) mice) or β1 (Thrb(PV) mice) also exhibit distinct phenotypes. These knockin mutant mice provide an opportunity to understand the molecular basis of isoform-dependent functions in vivo. Here we tested the hypothesis that the distinct functions of TR mutant isoforms are directed by a subset of nuclear regulatory proteins. Tandem-affinity chromatography of HeLa nuclear extracts showed that distinct 33 nuclear proteins including nuclear receptor corepressor (NCoR1) and six other proteins preferentially associated with TRα1PV or TRβ1PV, respectively. These results indicate that recruitment of nuclear regulatory proteins by TR mutants is subtype dependent. The involvement of NCoR1 in mediating the distinct liver phenotype of Thra1(PV) and Thrb(PV) mice was further explored. NCoR1 preferentially interacted with TRα1PV rather than with TRβ1PV. NCoR1 was recruited more avidly to the thyroid hormone response element-bound TRα1PV than to TRβ1PV in the promoter of the CCAAT/enhancer-binding protein α gene to repress its expression in the liver of Thra1(PV) mice, but not in Thrb(PV) mice. This preferential recruitment of NCoR1 by mutant isoforms could contribute, at least in part, to the distinct liver lipid phenotype of these mutant mice. The present study highlights a novel mechanism by which TR isoforms direct their selective functions via preferential recruitment of a subset of nuclear coregulatory proteins.

| S-EPMC3100599 | biostudies-literature

Thyroid hormone receptor isoform-specific modification by small ubiquitin-like modifier (SUMO) modulates thyroid hormone-dependent gene regulation.

Project description:Thyroid hormone receptor (TR) α and β mediate thyroid hormone action at target tissues. TR isoforms have specific roles in development and in adult tissues. The mechanisms underlying TR isoform-specific action, however, are not well understood. We demonstrate that posttranslational modification of TR by conjugation of small SUMO to TRα and TRβ plays an important role in triiodothyronine (T3) action and TR isoform specificity. TRα was sumoylated at lysines 283 and 389, and TRβ at lysines 50, 146, and 443. Sumoylation of TRβ was ligand-dependent, and sumoylation of TRα was ligand-independent. TRα-SUMO conjugation utilized the E3 ligase PIASxβ and TRβ-SUMO conjugation utilized predominantly PIAS1. SUMO1 and SUMO3 conjugation to TR was important for T3-dependent gene regulation, as demonstrated in transient transfection assay and studies of endogenous gene regulation. The functional role of SUMO1 and SUMO3 in T3 induction in transient expression assays was closely matched to the pattern of TR and cofactor recruitment to thyroid hormone response elements (TREs) as determined by ChIP assays. SUMO1 was required for the T3-induced recruitment of the co-activator CREB-binding protein (CBP) and release of nuclear receptor co-repressor (NCoR) on a TRE but had no significant effect on TR DNA binding. SUMO1 was required for T3-mediated recruitment of NCoR and release of CBP from the TSHβ-negative TRE. SUMO3 was required for T3-stimulated TR binding to the TSHβ-negative TRE and recruitment of NCoR. These findings demonstrate that conjugation of SUMO to TR has a TR-isoform preference and is important for T3-dependent gene induction and repression.

| S-EPMC3476315 | biostudies-literature

The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions.

Project description:The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid hormone response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 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.

| S-EPMC2681178 | biostudies-literature

The ability of thyroid hormone receptors to sense t4 as an agonist depends on receptor isoform and on cellular cofactors.

Project description:T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TR?1 generally more responsive to T4 than was TR?1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TR?1 nearly equally by T4 as by T3 in vitro, indicating that TR?1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoR?, from TR?1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.

| S-EPMC4004778 | biostudies-literature

Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor alpha1.

Project description:Thyroid hormone, via its nuclear receptors TRalpha and TRbeta, controls metabolism by acting locally in peripheral tissues and centrally by regulating sympathetic signaling. We have defined aporeceptor regulation of metabolism by using mice heterozygous for a mutant TRalpha1 with low affinity to T3. The animals were hypermetabolic, showing strongly reduced fat depots, hyperphagia and resistance to diet-induced obesity accompanied by induction of genes involved in glucose handling and fatty acid metabolism in liver and adipose tissues. Increased lipid mobilization and beta-oxidation occurred in adipose tissues, whereas blockade of sympathetic signaling to brown adipose tissue normalized the metabolic phenotype despite a continued perturbed hormone signaling in this cell type. The results define a novel and important role for the TRalpha1 aporeceptor in governing metabolic homeostasis. Furthermore, the data demonstrate that a nuclear hormone receptor affecting sympathetic signaling can override its autonomous effects in peripheral tissues.

| S-EPMC2063481 | biostudies-literature

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