Abstract
VULCAN utilises network analysis of genome-wide DNA binding data to predict regulatory interactions of transcription factors. We benchmarked our approach against alternative methods and found improved performance in all cases. VULCAN analysis of estrogen receptor (ER) activation in breast cancer highlighted key components of the ER signalling axis and identified a novel interaction with GRHL2, validated by ChIP-seq and quantitative proteomics. Mechanistically, we show E2-responsive GRHL2 binding occurs concurrently with increases in eRNA transcription and GRHL2 negatively regulates transcription at these sites. These findings provide new insight into ER action in breast cancer and validate VULCAN as a powerful tool.
Abbreviations
- AR
- Androgen Receptor
- ARACNe-AP
- AccuRate Algorithm for reConstruction of Network through Adaptive Partitioning
- CCLE
- Cancer Cell Line Encyclopedia
- ChIP
- Chromatin ImmunoPrecipitation
- ER
- Estrogen Receptor-Alpha
- ERE
- Estrogen-Response Elements
- GSEA
- Gene Set Enrichment Analysis
- GRHL2
- Grainyhead Like Transcription Factor 2
- METABRIC
- MolEcular TAxonomy of BReast cancer International Consortium
- PBS
- Phosphate Buffered Saline
- PI
- Protease Inhibitors
- PR
- Progesterone Receptor
- TCGA
- The Cancer Genome Atlas
- TF
- Transcription Factor
- VIPER
- Virtual Inference of Protein activity by Enriched Regulon analysis
- VULCAN
- VirtUaL ChIP-Seq Analysis through Networks
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.