Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression microarray screen for genes regulated by the unliganded glucocorticoid receptor

ABSTRACT: To further characterize the role of the unliganded glucocorticoid receptor (GR) in breast cells, we used an shRNA vector directed against GR to create EPH-4 mouse mammary cell lines with depleted endogenous levels of this receptor. RNA prepared from normal (EV-50) and GR-depleted (shGR-19) cells was used in an expression microarray screen for targets of unliganded GR. This analysis revealed 260 targets of negaive regulation by unliganded GR, and 343 targets of positive regulation by unliganded GR, several of which were involved in pro-apoptotic networks, and opposed the activity of liganded GR targets. This work presents the first screen for targets of unliganded GR. We propose that the balance between liganded and unliganded GR signaling is responsible for controlling differentiation and apoptosis, respectively, and suggest that gene regulation by unliganded GR may represent a mechanism of reducing the risk of breast tumourigenesis. RNA was prepared from EV-50 and shGR-19 cells and RNA integrity was determined using an Agilent 2100 Bioanalyzer. RNA was hybridized to the array in duplicate. The duplicates of each EV-50 and shGR-19 were averaged, and the shGR-19 data was subsequently compared to the EV-50 data.

ORGANISM(S): Mus musculus

SUBMITTER: Christopher Mueller

PROVIDER: E-GEOD-51408 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Expression microarray identifies the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells.

Ritter Heather D HD Mueller Christopher R CR

BMC cancer 20140422

<h4>Background</h4>While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes.<h4 ...[more]

PMID: 24755251

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Project description:Estrogen receptorï? beta (ER beta) has potent anti-proliferative and anti-inflammatory properties, suggesting that ER beta-selective agonists might be a new class of therapeutic and chemopreventative agents. To understand how ER beta regulates genes, we identified genes regulated by the unliganded and liganded forms of ER alpha and ER beta in U2OS cells. Microarray data demonstrated that virtually no gene regulation occurred with unliganded ER alpha, whereas many genes were regulated by estradiol (E2). These results demonstrate ER alpha requires a ligand to regulate a single class of genes. In contrast, ER beta regulated three classes of genes. Class I genes were regulated primarily by unliganded ER beta. Class II genes were regulated only with E2, whereas Class III genes were regulated by both unliganded ER beta and E2. There were 453 Class I genes, 258 Class II genes and 83 Class III genes. To explore the mechanism whereby ER beta regulates different classes of genes ChIP-seq was performed to identify ER beta binding sites and adjacent transcription factor motifs in regulated genes. AP1 binding sites were more enriched in Class I genes, whereas ERE, NFKB1 and SP1 sites were more enriched in class II genes. ER beta bound to all three classes of genes demonstrating that ER beta binding is not responsible for differential regulation of genes by unliganded and liganded ER beta. The coactivator, NCOA2 was differentially recruited to several target genes. Our findings indicate that the unliganded and liganded forms of ER beta regulate three classes of genes by interacting with different transcription factors and coactivators. U2OS cell lines are stably transfected with a doxycycline-inducible ER alpha or beta. 18 samples are analyzed with triplicate for each of the 6 conditions. The 6 conditions include ER alpha transfected without doxycycline added, ER alpha transfected with doxycycline added, ER alpha transfected with doxycycline added and E2 treatment, ER beta transfected without doxycycline added, ER beta transfected with doxycycline added, and ER beta transfected with doxycycline added and E2 treatment.

Dataset Information

Expression microarray screen for genes regulated by the unliganded glucocorticoid receptor

Publications

Expression microarray identifies the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells.

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