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NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

ABSTRACT: NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) 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 a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR). RNA was extracted from livers from 3 individual mice for each group (Double-floxed, Liver specific-SMRT knock out, and Liver specific-double knock out); all were euthyroid, female mice

ORGANISM(S): Mus musculus

SUBMITTER: Markus Jeitler

PROVIDER: E-GEOD-54192 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

Project description:NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) 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 a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR).

2014-11-21 | GSE54192 | GEO

Gene expression profiling in NCoR deficient mouse livers

Project description:The thyroid hormone receptor (TR) has been proposed to regulate target genes in the absence of triiodothyronine (T3), through the recruitment of the corepressors, NCoR and SMRT. NCoR and SMRT may thus play a key role in both hypothyroidism and resistance to thyroid hormone, though this has never been tested in vivo. To accomplish this we developed mice that express in the liver a NCoR protein (L-NCoR∆ID) that cannot interact with the TR. L-NCoR∆ID mice develop normally, however when made hypothyroid the repression of many positively regulated T3-target genes is abrogated, demonstrating that NCoR plays a specific and sufficient role in repression by the unliganded TR. Remarkably, in the euthyroid state, expression of many T3-targets are also upregulated in L-NCoR∆ID mice, demonstrating that NCoR also determines the magnitude of the response to T3 in euthyroid animals. While positive T3 targets were upregulated in L-NCoR∆ID mice in the hypo and euthyroid state there was less effect seen on negatively regulated T3 target genes. Thus, NCoR is a specific regulator of T3-action in vivo and mediates the activity of the unliganded TR. Furthermore, NCoR may play a key role in determining the differences in individual responses to similar levels of circulating T3. Keywords: NCoR, thyroid hormone signaling, mouse liver, DNA Microarray To better assess the role of NCoR in positive and negative regulation we performed micorarray analysis of gene expression in the livers of euthyroid and hypothyroid control and L-NCoR∆ID mice.

2008-12-03 | E-GEOD-10001 | biostudies-arrayexpress

Gene expression profiling in NCoR deficient mouse livers

2008-12-04 | GSE10001 | GEO

Corepressors NCOR1 and SMRT regulate metabolism via intestinal regulation of carbohydrate transport

Project description:Objective: Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT; also known as NCOR2). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity and energy expenditure and represent an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). Methods: We used a post-natal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically by assessing body weight, glucose levels and subjecting the mice to metabolic phenotyping, body composition analysis and glucose tolerance testing. IECs were isolated from the jejunum of the small intestine and profiled by bulk RNA sequencing. Results: We found that the post-natal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without any difference in food intake. This appeared to be driven by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2 and GLUT5. Conclusions: Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.

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Thyroid Hormone (TH) Controls The Remodeling Of The Pancreas And The Liver

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2010-05-16 | E-GEOD-16075 | biostudies-arrayexpress

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

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FOXO1 regulates a subset of thyroid hormone target genes

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Mus musculus

Project description:NCoR1 and SMRT play unique roles in thyroid hormone signaling in the liver

| PRJNA235393 | ENA

A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

Project description:Thyroid hormones (TH) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone- dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TR), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR, and defined high confidence binding sites where TR functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by TH have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, TH regulates gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.

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Characterization of Directly Regulated Thyroid Hormone Mediated Gene Expression Following Short-Term Perturbations in Thyroid Hormone Levels in Juvenile Mice

Project description:We investigated the effects of thyroid hormone disruptions on gene expression in juvenile mice liver to develop a stronger understanding of the mechanisms by which thyroid disrupting chemicals impair development. Gene expression was examined by hybridization of hepatic RNA to Agilent mouse microarrays for hyper-, hypo-, hypo-replacement (hypo+) and euthyroid animals. Keywords: Toxicogenomics, biomarkers of thyroid disruptors

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