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Series GSE60156 Query DataSets for GSE60156
Status Public on Dec 04, 2014
Title The oncogenic microRNA hsa-mir-155-5p targets the transcription factor ELK3 and links it to the hypoxia response and the Hypoxia Inducible Factor HIF1α
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels, including the transcriptional level by the Ets factor ELK3. The molecular mechanisms of this intimate transcriptional connection remain largely unknown. Whilst investigating global ELK3-chromatin interactions, we uncovered an unexpected connection that involves the microRNA hsa-miR-155-5p, a hypoxia-inducible oncomir that targets HIF1α. One of the ELK3 chromatin binding sites, detected by Chromatin Immuno-Precipitation Sequencing (ChIP-seq) of normal Human Umbilical Vein Endothelial Cells (HUVEC), is located at the transcription start site of the MIR155HG genes that expresses hsa-miR-155-5p. We confirmed that ELK3 binds to this promoter by ChIP and QPCR. We showed that ELK3 and hsa-miR-155-5p form a double-negative regulatory loop. ELK3 depletion induced hsa-miR-155-5p expression, and hsa-miR-155-5p expression decreased ELK3 expression at the RNA level through a conserved target sequence in its 3’-UTR. We further showed that the activities of hsa-miR-155-5p and ELK3 are functionally linked. Pathway analysis indicates that both factors are implicated in related processes, including cancer and angiogenesis. hsa-miR-155-5p expression and ELK3 depletion have similar effects on expression of known ELK3 target genes, and in-vitro angiogenesis and wound closure. Bioinformatic analysis of cancer RNA-seq data shows that hsa-miR-155-5p and ELK3 expression are significantly anti-correlated, as would be expected from hsa-miR-155-5p targeting ELK3 RNA. Hypoxia (0% oxygen) down-regulates ELK3 mRNA in a microRNA and hsa-miR-155-5p dependent manner. These results tie ELK3 into the hypoxia response pathway through an oncogenic microRNA and into a circuit implicated in the dynamics of the hypoxic response. This crosstalk could be important in the development of new treatments for a range of pathologies.
 
Overall design Examination of ELK3 DNA interactions in HUVEC cells under normal oxygen conditions
 
Contributor(s) Robertson ED, Wasylyk C, Ye T, Jung AC, Wasylyk B
Citation(s) 25401928
Submission date Aug 06, 2014
Last update date May 15, 2019
Contact name Tao YE
Organization name IGBMC (CNRS/INSERM/UDS)
Street address 1 rue Laurent Fries
City Illkirch
ZIP/Postal code 67404
Country France
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (2)
GSM1466691 ELK3 Normoxia
GSM1466692 input DNA
Relations
BioProject PRJNA257643
SRA SRP045302

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Supplementary file Size Download File type/resource
GSE60156_RAW.tar 1.7 Mb (http)(custom) TAR (of XLSX)
SRA Run SelectorHelp
Processed data provided as supplementary file
Raw data are available in SRA

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