GSE111914   Details

GSE Accession GSE111914
Title Hypoxic modulation of estrogen receptor alpha (ERα) transcriptional activity and binding to chromatin
Submission Date 3/15/18
Last Update Date 1/2/19
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Experiment Type Expression profiling by array
Contributor Charly,,Jehanno; Pascale Le Goff; Denis Habauzit; Yann Le Page; Sylvain Lecomte; Estelle Lecluse; Raphael Métivier; Denis Michel; Gilles Flouriot
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Summary A majority of breast tumors expresses estrogen receptor-α (ERα) whose activity is associated with hormone-dependent proliferation and survival and is exploited for hormone therapy. Understanding the etiological factors responsible for endocrine resistance in these tumors is a major challenge. Hypoxia, to which solid tumors are chronically exposed, has been shown to have a determinant role in the resistance to endocrine therapy. Several studies pointed out that it promotes ERα downregulation both in vitro and in vivo, yet consequences of hypoxic signaling on ERa activity remain largely elusive. In the present study, we show using a transcriptomic analysis that CoCl2 treatment mimicking hypoxia differentially affects the expression of ERα-responsive genes, some of them being strongly inhibited by hypoxia while others are upregulated. Chromatin immunoprecipitation of DNA coupled to high-throughput sequencing (ChIP-Seq) revealed a massive loss of ERα binding sites (ERBSs), which are preferentially located at vicinity of these hypoxia-inhibited genes. On the contrary, we detected a subset of ERα target genes being up-regulated by hypoxia. We suspect hypoxia-related transcription factors to interfere with ERα at the chromatin scale, as we detected ligand-independent enrichment of permissive histone mark H3K27ac in the regulatory sequences located near to these genes. Unexpectedly, ChIP-Seq analysis revealed enrichment in hypoxia-specific ERBSs, indicating partial redistribution of ERα cistrome. Taken together, our data define an important overlap of regulation between estrogenic signaling and hypoxia signaling, which might modulate hormone response in treatment.
Overall Design 4 replicates: Control MCF7 + EtOH; 4 replicates: Control MCF7 + E2; 4 replicates: Hypoxic MCF7 + EtOH; 4 replicates: Hypoxic MCF7 + E2; 4 replicates: Rescue MCF7 + EtOH; 4 replicates: Rescue MCF7 + E2
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