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Cross-talk between Estrogen Receptor-related Receptor alpha (ERRalpha) and Estrogen Receptor (ERalpha) pathways.

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE11266 | GEO | 2008/08/25

SECONDARY ACCESSION(S): PRJNA106665

REPOSITORIES: GEO

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Transcription profiling of human MCF7 cells were infected with adenovirus overexpressing one of the four proteins (PGC1 WT, PGC1 2x9, PGC1 L2L3 and BGAL) reveals cross-talk between Estrogen Receptor-related Receptor alpha (ERRalpha) and Estrogen Receptor (ERalpha) pathways.

Project description:Orphan nuclear receptor estrogen-related receptor alpha (ERRÎ±) has recently been shown to carry negative prognostic significance in breast and ovarian cancers. The specific role of ERRÎ± in tumor growth and progression, however, is yet to be fully understood. The significant homology between estrogen receptor alpha (ERÎ±) and ERRÎ± initially suggested that these receptors may share similar transcriptional targets. Using the well-characterized ERÎ±-positive MCF-7 breast cancer cell line, we sought to gain a genome-wide picture of ERÎ±-ERRÎ± cross-talk using an unbiased microarray approach. Since a small molecule ligand has not been identified for ERRÎ±, its transcriptional activity in these studies was induced using its known coactivator PGC-1Î± (peroxisome proliferator-activated receptor-Î³ coactivator-1Î±) 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-1Î± were controlled for using a variant PGC-1Î± 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

Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program [microarray: PGC1a_vs_GFP]

Project description:Skeletal muscle tissue shows an extraordinary cellular plasticity, but the underlying molecular mechanisms are still poorly understood. Here we use a combination of experimental and computational approaches to unravel the complex transcriptional network of muscle cell plasticity centered on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a regulatory nexus in endurance training adaptation. By integrating data on genome-wide binding of PGC-1α and gene expression upon PGC-1α over-expression with comprehensive computational prediction of transcription factor binding sites (TFBSs), we uncover a hitherto underestimated number of transcription factor partners involved in mediating PGC-1α action. In particular, principal component analysis of TFBSs at PGC-1α binding regions predicts that, besides the well-known role of the estrogen-related receptor α (ERRα), the activator protein-1 complex (AP-1) plays a major role in regulating the PGC-1α-controlled gene program of hypoxia response. Our findings thus reveal the complex transcriptional network of muscle cell plasticity controlled by PGC-1α.

2014-06-16 | GSE51189 | GEO

Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program [ChIP-Seq]

2014-06-16 | GSE51178 | GEO

Transcriptional network analysis in muscle reveals AP-1 as a partner of PGC-1α in the regulation of the hypoxic gene program [microarray: kD_AP1]

2014-06-16 | GSE51190 | GEO

The genomic context and co-recruitment of SP1 affect ERRα co-activation by PGC-1α in muscle cells [array]

Project description:The peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, e.g. by co-activating the estrogen-related receptor α (ERRα) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these two proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERRα to DNA in skeletal muscle cell line with elevated PGC-1α and linked the DNA recruitment to global PGC-1α target gene regulation. We found that, surprisingly, ERRα co-activation by PGC-1α is only observed in the minority of all PGC-1α recruitment sites. Nevertheless, a majority of PGC-1α target gene expression is dependent on ERRα. Intriguingly, the interaction between these two proteins is controlled by the genomic context of response elements, in particular the relative GC and CpG content, monomeric and dimeric repeat binding site configuration for ERRα, and adjacent recruitment of the transcription factor SP1. These findings thus not only reveal an unprecedented insight into the regulatory network underlying muscle cell plasticity, but also strongly link the genomic context of DNA response elements to control transcription factor - co-regulator interactions.

2016-04-22 | GSE80521 | GEO

The genomic context and co-recruitment of SP1 affect ERRα co-activation by PGC-1α in muscle cells [ChIP-Seq]

2016-04-22 | GSE80520 | GEO

The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-Folate Therapy in Breast Cancer [ChIP-Seq]

Project description:Reprogramming of cellular metabolism plays a central role in fuelling malignant transformation, and AMPK as well as the PGC-1α/ERRα axis are key regulators of this process. Intersection of gene expression and binding event datasets in breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer. We used microarrays to detail the global programme of gene expression following AMPK activation by AICAR in BT474 breast cancer cells.

2016-02-02 | GSE75876 | GEO

The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-Folate Therapy in Breast Cancer [Microarray expression]

Project description:Reprogramming of cellular metabolism plays a central role in fuelling malignant transformation, and AMPK as well as the PGC-1α/ERRα axis are key regulators of this process. Intersection of gene expression and binding event datasets in breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer. We used microarrays to detail the global program of gene expression following AMPK activation by AICAR in BT474 breast cancer cells.

2016-02-02 | GSE75727 | GEO

PGC-1a isoform-specific nuclear interactome

Project description:PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator-1alpha) coactivators regulate adaptive gene expression in response to challenges such as cold exposure, fasting, or physical exercise to balance energy supply and demand. Transcription of a single PGC-1α gene produces different isoforms (e.g. PGC-1α1 to α4) with different biological functions. We aimed to characterize the nuclear interactome for each PGC-1α variant, in particular the transcription factors they bind to regulate gene expression. This was done by generating GST-fusions of all PGC-1a variants, expressed in an insect cell system. These were used to capture associated protein complexes from HeLa nuclear extracts.

2022-03-01 | PXD009232 | Pride

PGC 1α Senses the CBC of Pre-mRNA to Dictate the Fate of Promoter-Proximally Paused RNAPII [RNA-seq]

Project description:Although PGC 1α is well-established as a transcriptional coactivator for the metabolic adaptation of mammalian cells to diverse physiological stresses, its molecular dynamics at the start and during gene transcription are incompletely understood. Previously, we defined a CBP80-binding motif (CBM) within PGC 1α that binds CBP80 at the 5′-cap of nascent transcripts deriving from PGC 1α-responsive genes. Binding verifies proper 5′-cap assembly, after which gene transcription is somehow promoted. Here, using protein immunoprecipitations, size-exclusion chromatography, PRO-seq, RNA-seq, native RIP-seq, RIP-seq footprinting and CUT&RUN, we report that PGC 1α, serving as a DNA−RNA conduit between promoter-bound ERRα and nascent transcript-bound CBP80, overcomes promoter-proximal pausing of RNAPII by competing against the premature transcription termination complex Integrator and also by recruiting P-TEFb. Using mice homozygous for five amino-acid changes in PGC 1α that destroy CBM function, we demonstrate that efficient differentiation of primary myoblasts to myofibers and effective regeneration of skeletal muscle after injury requires PGC 1α binding to CBP80.

2023-01-19 | GSE197311 | GEO

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