A Point Mutation in the Activation Function 2 Domain of Thyroid Hormone Receptor α1 Expressed after CRE-Mediated Recombination Partially Recapitulates Hypothyroidism

Quignodon, Laure; Vincent, Sophie; Winter, Harald; Samarut, Jacques; Flamant, Frédéric

doi:10.1210/me.2007-0176

Cited by 91 publications

(106 citation statements)

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“…6A) and assess both the influence of the mutation on TET3 interaction and dominant-negative property. TRα1 E403X (11) and TRα1 N359Y (12) have been found in two patients, and TRα1 L400R is lethal in a mouse knock-in model (13). As expected TRα N359Y and TRα1 L400R , but not TRα1 E403X , interacted with TET3-Cat (Fig.…”

Section: Tet Proteins Interact With Trsupporting

confidence: 74%

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Guan

Guyot

Samarut

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRα1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin.thyroid hormone receptor | methylcytosine dioxygenase TET3 | protein stability | chromatin recruitment | RTH syndrome T hyroid hormone (T3) is the main natural iodinated compound possessing a biological activity. It exerts a pleiotropic action on development and homeostasis, acting on most, if not all, cell types (1). T3 acts directly on gene transcription by binding to the thyroid hormone receptors (TRs) TRα1, TRβ1, and TRβ2. They are, respectively, encoded by the THRA and THRB genes. In humans, mutations of either THRA or THRB cause the resistance to thyroid hormone syndrome (RTH). The severity of the disease is determined by the precise location of the mutation (2), dictating the ability of the mutated TR to respond to T3 (3).TRs, as the other members of the nuclear receptor superfamily, are ligand-regulated transcription factors consisting of three major functional domains: the amino-terminal A/B domain, the DNAbinding domain, and the ligand-binding domain. TRs can bind to DNA on a TR response element (TRE) the in absence of T3, and on most genes they repress transcription until T3 binds and leads to activation. Helix12 is the major structural element associated with this process. T3 triggers a dramatic shift of its position, leading to dissociation of corepressors and recruitment of coactivators, including coactivators that have the ability to change the chromatin microenvironment (4). T3 binding also induces a rapid proteasomemediated degradation of TRs that is associated with T3-dependent transcriptional activity (5). TR availability and chromatin access are thus possibly important levels of modulation of T3 cellular response.The goal of the present study was to identify epigenetic regulators that interact with, and therefore may modulate, TR transcriptional activity, using in vitro pull-down screening. This approach allowed us to identify TET3, a member of the ten-eleven translocation (TET) family proteins, as a partner for TRs....

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Section: Tet Proteins Interact With Trsupporting

confidence: 74%

Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Guan

Guyot

Samarut

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…This evidence further strengthens the hypothesis that TR play roles in fetal brain development and maturation, especially within the hippocampus, and in maintaining adult brain function (Bernal 2007). Further insights into phenotypic differences between these mutant mice strains are of particular interest, with additional work now being conducted in generating cell-specific TR mutant models (Quignodon et al 2007, Flamant & Quignodon 2010. TRs have also been observed within the cytosol, where they interact with p85, a regulatory subunit of phosphatidylinositol 3-kinase (Moeller et al 2006).…”

Section: Tr Genes and Activitymentioning

confidence: 99%

Thyroid hormones and fetal neurological development

Patel¹,

Landers²,

Li³

et al. 2011

Journal of Endocrinology

186

126

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The development of fetal thyroid function is dependent on the embryogenesis, differentiation, and maturation of the thyroid gland. This is coupled with evolution of the hypothalamic-pituitary-thyroid axis and thyroid hormone metabolism, resulting in the regulation of thyroid hormone action, production, and secretion. Throughout gestation there is a steady supply of maternal thyroxine (T 4 ) which has been observed in embryonic circulation as early as 4 weeks post-implantation. This is essential for normal early fetal neurogenesis. Triiodothyronine concentrations remain very low during gestation due to metabolism via placental and fetal deiodinase type 3. T 4 concentrations are highly regulated to maintain low concentrations, essential for protecting the fetus and reaching key neurological sites such as the cerebral cortex at specific developmental stages. There are many known cell membrane thyroid hormone transporters in fetal brain that play an essential role in regulating thyroid hormone concentrations in key structures. They also provide the route for intracellular thyroid hormone interaction with associated thyroid hormone receptors, which activate their action. There is a growing body of experimental evidence from rats and humans to suggest that even mild maternal hypothyroxinemia may lead to abnormalities in fetal neurological development. Our review will focus on the ontogeny of thyroid hormone in fetal development, with a focus on cell membrane transporters and TR action in the brain.

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“…Only recently has the generation of a mouse mutant been reported that allows the expression of a mutated receptor form in a cell-specific manner. These mice mutants carry a floxed point mutation in the activation domain of TRalpha1 (TRalpha1L400R) that is only active after a Cre-induced recombination event (Flamant and Quignodon, 2009;Quignodon et al, 2007b). This mutation favours the permanent recruitment of corepressors by interfering the interaction with histone acetyl transferase.…”

Section: Role Of Thyroid Hormone Receptorsmentioning

confidence: 99%

“…Therefore, such a mutated receptor form may act in a dominant negative manner. Indeed, inducing the early expression of this mutated receptor results in a phenotype that recapitulates many aspects of congenital hypothyroidism excluding those effects that are due to a repressed activation of thyroid hormone receptor beta forms (Quignodon et al, 2007b). Noteworthy is the fact that the cerebellar granule cell differentiation pattern resembles that of hypothyroid animals whereas Purkinje cell dendritogenesis is only temporarily delayed suggesting that the developmental increase in TRbeta expression in Purkinje cells might counterbalance to a certain degree the repressive mode of TRalpha1.…”

Section: Role Of Thyroid Hormone Receptorsmentioning

confidence: 99%