Triiodothytonine (T3) response is changed after KLF9 knockdown in HepG2-TRbeta overexpressing cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE54699 | GEO | 2014/12/31
SECONDARY ACCESSION(S): PRJNA237447
REPOSITORIES: GEO
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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/ Krüppel-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)
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Project description:We used an integrated genomics approach to profile and characterize the cistrome of TR-beta, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3 in a normal thyroid cell line. Our data demonstrates that T3 promotes significant shifts in TR-beta genomic occupancy, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers.
2021-04-01 | GSE168952 | GEO
Project description:We used an integrated genomics approach to profile and characterize the cistrome of TR-beta, map changes in chromatin accessibility, and capture the transcriptomic changes in response to T3 in a normal thyroid cell line. Our data demonstrates that T3 promotes significant shifts in TR-beta genomic occupancy, which are associated with differential chromatin accessibility, and differential recruitment of SWI/SNF chromatin remodelers.
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Project description:Krueppel-like factor 9 (Klf9) is a DNA-binding transcription factor that has been implicated in neuronal development and regeneration. We used mouse hippocampus-derived HT22 cell line to identify genes differentially regulated by forced Klf9 expression. We stably transfected HT22 cells with pCDNA6:TR (encoding the Tet repressor) and pCDNA6:TO-Klf9 (encoding Klf9 downstream of the Tet operator), allowing doxycycline(dox)-inducible expression of Klf9. We chose a stably transfected clone with baseline Klf9 mRNA level similar to that of untransfected HT22 cells (parent line) and approximately 10-fold induction after dox treatment. We conducted RNA-seq on stably transfected HT22 cells treated with or without dox for 8 hours; we also conducted RNA-seq on parent cells subjected to the same dox treatment to separate nonspecific effects of dox from the effects of forced Klf9 expression. Analysis of RNA-seq data found 217 gene repressed and 21 upregulated by forced Klf9 expression (FDR-adjusted p<.005; because fold changes were small we used a stringent p value cutoff to ensure that we were studying genes likely to be bona fide targets), showing that Klf9 functions primarily as a transcriptional repressor. Gene ontology analysis showed that Klf9-repressed genes were enriched in cytoskeletal and Wnt signaling-related genes.
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Project description:Hypothyroids wild type and TRbeta -/- mice were treated with T3 and livers were collected and analysed using a microarray with 6500 cDNA probes. Expression ratios were calulated between 1) hypothyroids WT and TRbeta-/- mice 2) hypothyroid WT and hypothyroid TR beta-/- mice treated with T3 and 3) hypothyroid TRbeta-/- and hypothyroid TRbeta-/- treated with T3. Keywords: other
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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].
2011-10-31 | E-GEOD-32444 | biostudies-arrayexpress
Project description:Hypothyroids wild type and TRbeta -/- mice were treated with T3 and livers were collected and analysed using a microarray with 6500 cDNA probes. Expression ratios were calulated between 1) hypothyroids WT and TRbeta-/- mice 2) hypothyroid WT and hypothyroid TR beta-/- mice treated with T3 and 3) hypothyroid TRbeta-/- and hypothyroid TRbeta-/- treated with T3.
2010-06-10 | E-GEOD-2490 | biostudies-arrayexpress
Project description:Analysis of change in transcriptosome after TRα or TRβ knockdown in hADSC. Analysis of effects of siRNA transfection (siCtrl, siTRα, siTRβ or siETV5) in hADSC at gene expression level.The hypothesis tested in the present study was that unliganded TRα and TRβ have distinctive roles in these cells. Total RNA was obtained from hADSC, transfected with siCtrl, siTRα, siTRβ or ETV5. siTRα, siTRβ or siETV5 samples were compared to siCtrl samples.
2016-10-26 | E-GEOD-75692 | biostudies-arrayexpress