Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of mouse hearts from mutants lacking estrogen-related receptor alpha (ERRalpha), a nuclear receptor

ABSTRACT: Total RNA was isolated from 3 WT and 3 ERRalpha null hearts and independent hybridizations were performed using MOE430 2.0 microarrays. Expression profiling was conducted to determine changes in gene expression in hearts lacking ERRa. The expression of genes involved in heart and muscle development, muscle contraction, lipid metabolism, OxPhos, protein metabolism and transcription were affected by the loss of ERRa. Experiment Overall Design: 3 hearts from WT and 3 hearts from ERRalpha-null mice were used in the study. The expression of genes in the ERRalpha KO hearts were compared to the reference WT hearts.

ORGANISM(S): Mus musculus

SUBMITTER: Vincent Giguere

PROVIDER: E-GEOD-7196 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.

Dufour Catherine R CR Wilson Brian J BJ Huss Janice M JM Kelly Daniel P DP Alaynick William A WA Downes Michael M Evans Ronald M RM Blanchette Mathieu M Giguère Vincent V

Cell metabolism 20070501 5

Orphan nuclear receptor ERRalpha (NR3B1) is recognized as a key regulator of mitochondrial biogenesis, but it is not known whether ERRalpha and other ERR isoforms play a broader role in cardiac energetics and function. We used genome-wide location analysis and expression profiling to appraise the role of ERRalpha and gamma (NR3B3) in the adult heart. Our data indicate that the two receptors, acting as nonobligatory heterodimers, target a common set of promoters involved in the uptake of energy s ...[more]

PMID: 17488637

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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.

Dataset Information

Transcription profiling of mouse hearts from mutants lacking estrogen-related receptor alpha (ERRalpha), a nuclear receptor

Publications

Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.

Similar Datasets

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