Identification of ERRalpha dependent PGC-1alpha tagret genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE5968 | GEO | 2006/11/10
SECONDARY ACCESSION(S): PRJNA97437
REPOSITORIES: GEO
Similar Datasets
Project description:PGC-1 transcription factor was customized to limit its interations to ERRalpha. This mutant (2x9) was used to dissect the transcription activation patterns that are attributable to the PGC1-ERR interaction and PGC-1 actions that are independent of ERR. Inactive mutant with the deleted LLXXL motifs (L2L3) and wt PGC-1 were used as negative and positive controls respectively. BGAL-expressing construct was used to control for non-specific effects of adenoviral infection. Experiment Overall Design: Expression constructs for BGAL control and three variants of PGC-1 were introduced into HepG2 cells via adenoviral infection. RNA was isolated 24 hrs post infection and the changes in gene expression were detected using GeneChip technology (Affymetrix). Hybridization was performed on the HG-133 plus 2 platform. The experiment was performed in three biological replicates. Raw expression data were normalized using MAS5.0 algorithm.
2008-06-14 | E-GEOD-5968 | biostudies-arrayexpress
Project description:Orphan nuclear receptor estrogen-related receptor alpha (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of ERRα in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERα) and ERRα initially suggested that these receptors may share similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. Since a small molecule ligand has not been identified for ERRα, its transcriptional activity in these studies was induced using its known coactivator PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) as a protein ligand. Both wild-type PGC1, as well as ERRa-specific variant (PGC1 2x9) were used to activate ERRa. Non-NR-dependent activities of PGC-1α were controlled for using a variant PGC-1α in which the leucines within the NR-interacting domain had been mutated to alanines (L2L3M). Beta-galactosidase (BGAL) overexpression was used as a non-specific background control. Activation of endogenous ER was achieved by treatment with 10 nM estadiol. Experiment Overall Design: MCF7 cells were infected with adenovirus overexpressing one of the four proteins (PGC1 WT, PGC1 2x9, PGC1 L2L3 and BGAL); Twelve hours post infection cells were then treated with either 10 nM estradiol (E2)or ethanol vehicle for 12 hours. Each combination of infection and treatment was was repeated three times in three independent experiments. A total of 23 samples are presented. Two replicates instead of three are shown for PGC1 WT E2 for technical reasons.
2008-10-25 | E-GEOD-11266 | biostudies-arrayexpress
Project description:This dataset is part of the manuscript titled "The metabolic regulator ERRalpha, a downstream target of HER2/IGF1, as a therapeutic target in breast cancer" (in review). The expression data obtained in human mammary epithelial cells were used to generate a list of ERRalpha-regulated genes that was later refined in clinical breast cancer datasets to generate a clinically relevant signature of ERalpha activity (referred to as Cluster 3 signature). Using this signature of the estrogen-related receptor alpha (ERRa) to profile more than eight-hundred breast tumors, we found that patients with tumors exhibiting higher ERRa activity were predicted to have shorter disease free survival. Further, the ability of an ERRa antagonist, XCT790, to inhibit breast cancer cell proliferation correlates with the cellâs intrinsic ERRa activity. These findings highlight the potential of using the ERRa signature and antagonists in targeted therapy for breast cancer. Using a chemical genomic approach we determined that activation of the HER2/IGF1 signaling pathways upregulates the expression of PGC-1b, an obligate cofactor for ERRa activity. Knockdown of PGC-1b in HER2 positive breast cancer cells impaired ERRa signaling and reduced cell proliferation, implicating a functional role of PGC1b/ERRa in the pathogenesis HER2 positive breast cancer. Primary human mammary epithelial cells were a gift from Dr. J. Marks (Duke University, Durham, NC) and cultured in MEBM (Cambrex, East Rutherford, NJ) with MEGM bullet kit and supplemented with 5mg/ml transferrin and 10-5M isoproterenol. To generate ERR-alpha signature, hMECs were serum starved for 36h followed by infection with MOI=150 of adenoviruses expressing two variants of PGC1alpha, a protein ligand for ERRalpha: PGC-1alpha2x9 or PGC-1alpha L2L3M. PGC-1-2x9 is specific to ERRalpha, while PGC-1-L2L3M lacks the NR box and does not interact with ERRalpha or other nuclear receptors. The generation and purification of variant PGC-1alpha viruses were described previously (Gaillard et al., Molecular Cell 24:5, 2006). Comparable expression levels of the two PGC-1alpha variants were verified by Western immonoblot analysis (data not shown). RNA was collect 16h after infection and purified using RNeasy mini kit (Qiagen, Valencia, CA). Ten independent biological replicates from each virus infection were collected.
2010-11-01 | E-GEOD-23061 | biostudies-arrayexpress
Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases. Gene expression of a total of 20 gastrocnemius samples from control (CON, n = 5), NCoR1 muscle-specific knockout (NCoR1 MKO, n = 5), wild type (WT, n = 5) and PGC-1alpha muscle-specific transgenic (PGC-1alpha mTg, n = 5) adult male mice was analyzed using GeneChip® Gene 1.0 ST Array System (Affymetrix). NCoR1 MKO and PGC-1alpha mTg samples were compared to CON and WT samples, respectively.
2013-01-08 | E-GEOD-40439 | biostudies-arrayexpress
Project description:Orphan nuclear receptor estrogen-related receptor alpha (ERRα) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of ERRα in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERα) and ERRα initially suggested that these receptors may share similar transcriptional targets. Using the well-characterized ERα-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERα-ERRα cross-talk using an unbiased microarray approach. Since a small molecule ligand has not been identified for ERRα, its transcriptional activity in these studies was induced using its known coactivator PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) as a protein ligand. Both wild-type PGC1, as well as ERRa-specific variant (PGC1 2x9) were used to activate ERRa. Non-NR-dependent activities of PGC-1α were controlled for using a variant PGC-1α in which the leucines within the NR-interacting domain had been mutated to alanines (L2L3M). Beta-galactosidase (BGAL) overexpression was used as a non-specific background control. Activation of endogenous ER was achieved by treatment with 10 nM estadiol. Keywords: Response to stimulus
2008-08-25 | GSE11266 | GEO
Project description:In the present study we have studied the mechanistic and functional aspects of NCoR1 function in mouse skeletal muscle. NCoR1 muscle-specific knockout mice exhibited an increased oxidative metabolism. Global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC-1alpha) overexpression on oxidative metabolism in skeletal muscle. The repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1alpha-mediated coactivation of ERRalpha. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.
2013-01-08 | GSE40439 | GEO
Project description:We found that TLS can work as a PGC-1alpha cofactor and this assay was carried out to test the functional dependency of TLS on PGC-1alpha on a whole genome scale
2013-07-26 | GSE23242 | GEO
Project description:PGC-1alpha; is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha; are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta; is elevated in the livers of these mice and activates the gluconeogenic genes in a PGC-1α-independent manner. Despite having reduced mitochondrial function, PGC-1alpha; null mice are paradoxically lean and resistant to diet-induced obesity. This is largely due to a profound hyperactivity displayed by the null animals and is associated with lesions in the striatal region of the brain that controls movement. These data illustrate a central role for PGC-1alpha; in the control of energy metabolism but also reveal novel systemic compensatory mechanisms and pathogenic effects of impaired energy homeostasis.
2007-04-06 | E-CBIL-22 | biostudies-arrayexpress
Project description:Mitochondrial oxidative function is tightly controlled to maintain energy homeostasis in response to nutrient and hormonal signals. An important cellular component in the energy sensing response is the target of rapamycin (TOR) kinase pathway; however whether and how mTOR controls mitochondrial oxidative activity is unknown. Here, we show that mTOR kinase activity stimulates mitochondrial gene expression and oxidative function. In skeletal muscle cells and TSC2-/- MEFs, the mTOR inhibitor rapamycin largely decreased gene expression of mitochondrial transcriptional regulators such as PGC-1alpha and the transcription factors ERRalpha and NRFs. As a consequence, mitochondrial gene expression and oxygen consumption were reduced upon mTOR inhibition. Using computational genomics, we identified the transcription factor YY1 as a common target of mTOR and PGC-1alpha that controls mitochondrial gene expression. Inhibition of mTOR resulted in a failure of YY1 to interact and be coactivated by PGC-1alpha. Notably, knock-down of YY1 in skeletal muscle cells caused a significant decrease in mRNAs of mitochondrial regulators and mitochondrial genes that resulted in a decrease in respiration. Moreover, YY1 was required for rapamycin-dependent repression of mitochondrial genes. Thus, we have identified a novel mechanism in which a nutrient sensor (mTOR) balances energy metabolism via transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. Experiment Overall Design: Using Affymetrix MOE430 v2 gene chips, biological triplicates of each condition were analyzed: vehicle-treated, rapamycin-treated, gfp-infected, and pgc-1alpha-infected resulting in a total of 12 samples. Experiment Overall Design: Data were analyzed by RMA (with default settings) in BioConductor 1.2 -- one batch for the Rapamycin vs. Vehicle, and another batch for the PGC vs GFP.
2008-06-13 | E-GEOD-5332 | biostudies-arrayexpress
Project description:Mitochondrial oxidative function is tightly controlled to maintain energy homeostasis in response to nutrient and hormonal signals. An important cellular component in the energy sensing response is the target of rapamycin (TOR) kinase pathway; however whether and how mTOR controls mitochondrial oxidative activity is unknown. Here, we show that mTOR kinase activity stimulates mitochondrial gene expression and oxidative function. In skeletal muscle cells and TSC2-/- MEFs, the mTOR inhibitor rapamycin largely decreased gene expression of mitochondrial transcriptional regulators such as PGC-1alpha and the transcription factors ERRalpha and NRFs. As a consequence, mitochondrial gene expression and oxygen consumption were reduced upon mTOR inhibition. Using computational genomics, we identified the transcription factor YY1 as a common target of mTOR and PGC-1alpha that controls mitochondrial gene expression. Inhibition of mTOR resulted in a failure of YY1 to interact and be coactivated by PGC-1alpha. Notably, knock-down of YY1 in skeletal muscle cells caused a significant decrease in mRNAs of mitochondrial regulators and mitochondrial genes that resulted in a decrease in respiration. Moreover, YY1 was required for rapamycin-dependent repression of mitochondrial genes. Thus, we have identified a novel mechanism in which a nutrient sensor (mTOR) balances energy metabolism via transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer. Keywords: comparative genomics, drug treatment response
2007-12-01 | GSE5332 | GEO