Thyroid Hormone Signaling <i>In Vivo</i> Requires a Balance between Coactivators and Corepressors

Vella, Kristen R.; Ramadoss, Preeti; Costa-e-Sousa, Ricardo H.; Astapova, Inna; Ye, Felix D; Holtz, Kaila A.; Harris, Jonathan M.; Hollenberg, Anthony N.

doi:10.1128/mcb.00129-14

Cited by 46 publications

(34 citation statements)

References 63 publications

(116 reference statements)

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“…While classical models suggest that the corepressors are mainly recruited by the unliganded TR, the mechanisms by which T3 coordinates specific signaling in the liver both positively and negatively are still unknown (3). Indeed, recent work by our laboratory and others has demonstrated that the corepressors appear to play a critical role in mediating ligand sensitivity regardless of the concentration of ligand (4)(5)(6)(7).…”

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confidence: 99%

NCoR1 and SMRT Play Unique Roles in Thyroid Hormone Action In Vivo

Shimizu

Astapova

et al. 2015

Molecular and Cellular Biology

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c NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors; NCoR2) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated mice that lacked function of either NCoR1, SMRT, or both in the liver only and additionally a global SMRT knockout model. Despite both corepressors being present in the liver, deletion of SMRT in either euthyroid or hypothyroid animals had little effect on TH signaling. In contrast, disruption of NCoR1 action confirmed that NCoR1 is the principal mediator of TH sensitivity in vivo. Similarly, global disruption of SMRT, unlike the global disruption of NCoR1, did not affect TH levels. While SMRT played little role in TH-regulated pathways, when disrupted in combination with NCoR1, it greatly accentuated the synthesis and storage of hepatic lipid. Taken together, these data demonstrate that corepressor specificity exists in vivo and that NCoR1 is the principal regulator of TH action. However, both corepressors collaborate to control hepatic lipid content, which likely reflects their cooperative activity in regulating the action of multiple NRs including the TH receptor (TR).T hyroid hormone (TH) is one of the most important metabolic regulators in humans, and its actions in the liver include the regulation of cholesterol and lipid metabolism. Thyroxine (T4) is the major circulating form of thyroid hormone, and it is converted to its active form, triiodothyronine (T3), by a family of deiodinases (1). T3 regulates metabolic processes via thyroid hormone receptor (TR) isoforms that are expressed in all peripheral tissues, including liver. The TRs mediate target gene regulation by recruiting a constellation of coregulators that include corepressors (CoRs) and coactivators depending upon the presence of T3 (2). While classical models suggest that the corepressors are mainly recruited by the unliganded TR, the mechanisms by which T3 coordinates specific signaling in the liver both positively and negatively are still unknown (3). Indeed, recent work by our laboratory and others has demonstrated that the corepressors appear to play a critical role in mediating ligand sensitivity regardless of the concentration of ligand (4-7).The two principal corepressors that are suggested to be involved in mediating TH action are nuclear receptor corepressor 1 (NCoR1) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) (4). They are highly homologous modular proteins and have three similar nuclear receptor (NR) interaction domains (NRIDs) at their C termini (8). Importantly, whole-body gene knockouts (KOs) of NCoR1 or SMRT result in embryonic lethality, but mutation or deletion of only the NRIDs allows for full development (6, 9, 10). In NCoR⌬ID mice, which express an altered NCoR1 allele that lacks the N3 and N2 NRIDs, there is evidence for increased thyroid hormone sensitivity...

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NCoR1 and SMRT Play Unique Roles in Thyroid Hormone Action In Vivo

Shimizu

Astapova

et al. 2015

Molecular and Cellular Biology

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“…The negative regulation of TRH and TSH synthesis has long been recognized, but the mechanism is still under study (Segerson et al 1987, Guissouma et al 2000, Hollenberg 2008, Chiamolera et al 2012, Vella et al 2014. T 3 binds to TH receptors (THRs) THRa1, or THRb1 and THRb2, that are expressed and regulated in a tissuespecific manner; the same receptor may stimulate or inhibit transcription of multiple proteins in the same tissue .…”

Section: Trh Biosynthesismentioning

confidence: 99%

Regulation of TRH neurons and energy homeostasis-related signals under stress

Joseph‐Bravo

Jaimes-Hoy

Charlí

2015

Journal of Endocrinology

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Energy homeostasis relies on a concerted response of the nervous and endocrine systems to signals evoked by intake, storage, and expenditure of fuels. Glucocorticoids (GCs) and thyroid hormones are involved in meeting immediate energy demands, thus placing the hypothalamo-pituitary-thyroid (HPT) and hypothalamo-pituitary-adrenal axes at a central interface. This review describes the mode of regulation of hypophysiotropic TRHergic neurons and the evidence supporting the concept that they act as metabolic integrators. Emphasis has been be placed on i) the effects of GCs on the modulation of transcription of Trh in vivo and in vitro, ii) the physiological and molecular mechanisms by which acute or chronic situations of stress and energy demands affect the activity of TRHergic neurons and the HPT axis, and iii) the less explored role of non-hypophysiotropic hypothalamic TRH neurons. The partial evidence gathered so far is indicative of a contrasting involvement of distinct TRH cell types, manifested through variability in cellular phenotype and physiology, including rapid responses to energy demands for thermogenesis or physical activity and nutritional status that may be modified according to stress history.

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“…Remarkably, when Src1 −/− were crossed with N-CoRΔID animals, the resulting compound knockout mice had normal circulating TH and TSH levels and normal ability to suppress TSH in response to T 3 treatment, thus demonstrating reversal of resistance present in Src1-deficient mice (Vella et al 2014). Additionally, T 3 -mediated upregulation of positive TR target genes in the liver, which is blunted in Src1 −/− mice, was restored in NCoRΔID Src1 −/− animals.…”

Section: Ncor-dadmmentioning

confidence: 95%

“…Intact Src1 function is also required for full TH sensitivity at least in some peripheral tissues as upregulation of positive TH targets in response to T 3 is blunted in the liver of Src1 −/− mice. However, normal regulation of gene expression was observed in the heart (Vella et al 2014). TR isoform-specific Src1 function was also assessed in compound Thra/Src1 and Thrb/Src1 knockout mice during TH deprivation and TH treatment.…”

Section: Src1 Knockout Micementioning

confidence: 99%

“…SMRT and SRC2 appear to be a 'second-tier' co-regulator and can only minimally, if at all, compensate for the absence of NCoR and SRC1 in the context of TH signaling. In fact, the role of SMRT and SRC2 only becomes apparent in the compound knockout models, such as Src1 −/− /Src2 −/− , L-NCoRΔID/Smrt −/− (Shimizu et al 2015), and NCoRΔID/Src1 −/− (Vella et al 2014).…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

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Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

Astapova¹

2016

Journal of Molecular Endocrinology

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Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T 3 )-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T 3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T 3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T 3 , local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis.

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Thyroid Hormone Signaling In Vivo Requires a Balance between Coactivators and Corepressors

Cited by 46 publications

References 63 publications

NCoR1 and SMRT Play Unique Roles in Thyroid Hormone Action In Vivo

NCoR1 and SMRT Play Unique Roles in Thyroid Hormone Action In Vivo

Regulation of TRH neurons and energy homeostasis-related signals under stress

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

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