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Gene expression profiling in NCoR deficient mouse livers

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE10001 | GEO | 2008/12/04

SECONDARY ACCESSION(S): PRJNA108181

REPOSITORIES: GEO

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Project description:Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRMs) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver and insulin resistance in preclinical animal models. STRMs differ from native THs in preferential binding to the TR? subtype versus TR?, increased uptake into liver and reduced uptake into other tissues. However, selective modulators of other nuclear receptors (NRs) exhibit important gene-selective actions which have been attributed to differential effects on receptor conformation and dynamics and these effects can have profound influences in animals and humans. While there are suggestions that STRMs could exhibit such gene-specific actions, the extent to which these effects are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, triiodothyronine (T3), and the prototype STRM GC-1 induce identical gene-sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TR?, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency versus T3, at angiopoietin-like factor 4 (ANGPTL4) in HepG2. Investigation of the latter effect confirms that GC-1 acts through TR? to directly induce this gene. However, this gene-selective GC-1 activity is not related to unusual T3 response element (TRE) sequence, unlike previously documented promoter-selective STRM actions. Together, our data suggest that T3 and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRMs will be subtle and rare. We treated 9-week old euthyroid male C57/Bl6 mice with vehicle or ligand (T3 or GC-1) by a single oral gavage (n=5 per treatment) and also performed a similar study in which mice were first made hypothyroid by two week feeding on iodine deficient diet (n=3-4 per treatment), analyzing mRNA 24h post treatment [Illumina]. We also treated HepG2 with vehicle or 10nM ligand (T3 or GC1; n=3 / treatment), analyzing mRNA 24h post treatment [Affymetrix].

Project description:Thyroid hormone receptors (TRs) represent important regulators of development, homeostasis, cell proliferation and differentiation. Here we investigated the impact of thyroid hormone (T3) on growth and differentiation of human red blood cells. T3 was found to effectively accelerate differentiation of SCF/Epo dependent red cell progenitors in vitro concomitantly with inducing growth arrest. This T3 activity was further enhanced by 9-cis retinoic acid (9cRA) that activates retinoid X receptor (RXR), the obligate heterodimeric partner of TR. To identify molecular targets for T3 activity in red cells, we employed a genome wide approach with DNA microarrays. We demonstrate that T3 and 9cRA induces specific gene expression patterns of up-or down-regulated genes, including ALAD and GATA-2, respectively. This study also revealed gene clusters, indicating accelerated differentiation in response to treatment. Mining for T3 induced genes identified BTEB1 (KLF9) and GAR22 as TR target genes. BTEB1/ KLF9 (basic transcription element binding protein 1/ KrÃ¼ppel-like factor 9) is a known TR target gene. GAR22 (growth arrest specific 2 (GAS2)-related gene on chromosome 22), initially found as a putative tumor suppressor gene, was induced by T3 also in the presence of cycloheximide, identifying it as a direct target of TR. Thus, our study uncovers novel targets of TR action with a potential function in T3 induced differentiation and growth arrest of red cell progenitors. Experiment Overall Design: 13 hybridizations in two individual experiments. Experiment Overall Design: Experiment 1: Experiment Overall Design: 1_SCF/Epo, 1_Epo/insulin(8h), 1_Epo/insulin(24h), 1_Epo/insulin(48h) Experiment Overall Design: Experiment 2: Experiment Overall Design: 2_SCF/Epo, 2_Epo/insulin(8h), 2_Epo/insulin(24h), 2_Epo/insulin(48h) Experiment Overall Design: 2_Epo/insulin+T3(8h), 2_Epo/insulin+9cRA(8h) Experiment Overall Design: 2_Epo/insulin+T3+9cRA(8h), , 2_Epo/insulin+T3+9cRA(24h), 2_Epo/insulin+T3+9cRA(48h)

Project description:Synthetic selective thyroid hormone (TH) receptor (TR) modulators (STRMs) exhibit beneficial effects on dyslipidemias in animals and humans and reduce obesity, fatty liver and insulin resistance in preclinical animal models. STRMs differ from native THs in preferential binding to the TRβ subtype versus TRα, increased uptake into liver and reduced uptake into other tissues. However, selective modulators of other nuclear receptors (NRs) exhibit important gene-selective actions which have been attributed to differential effects on receptor conformation and dynamics and these effects can have profound influences in animals and humans. While there are suggestions that STRMs could exhibit such gene-specific actions, the extent to which these effects are actually observed in vivo has not been explored. Here, we show that saturating concentrations of the main active form of TH, triiodothyronine (T3), and the prototype STRM GC-1 induce identical gene-sets in livers of euthyroid and hypothyroid mice and a human cultured hepatoma cell line that only expresses TRβ, HepG2. We find one case in which GC-1 exhibits a modest gene-specific reduction in potency versus T3, at angiopoietin-like factor 4 (ANGPTL4) in HepG2. Investigation of the latter effect confirms that GC-1 acts through TRβ to directly induce this gene. However, this gene-selective GC-1 activity is not related to unusual T3 response element (TRE) sequence, unlike previously documented promoter-selective STRM actions. Together, our data suggest that T3 and GC-1 exhibit almost identical gene regulation properties and that gene-selective actions of GC-1 and similar STRMs will be subtle and rare. We treated HepG2 with vehicle or 10nM ligand (T3 or GC1; n=3 / treatment), analyzing mRNA 24h post treatment [Affymetrix]. We also treated 9-week old euthyroid male C57/Bl6 mice with vehicle or ligand (T3 or GC-1) by a single oral gavage (n=5 per treatment) and also performed a similar study in which mice were first made hypothyroid by two week feeding on iodine deficient diet (n=3-4 per treatment), analyzing mRNA 24h post treatment [Illumina].

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Gene expression profiling in NCoR deficient mouse livers

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