Abstract
Background VirtUaL ChIP-seq Analysis through Networks (VULCAN) infers regulatory interactions of transcription factors by overlaying networks generated from publicly available tumor expression data onto ChIP-seq data. We applied our method to dissect the regulation of Estrogen Receptor-alpha (ER) activation in breast cancer to identify potential coregulators of the ER’s transcriptional response.
Results VULCAN analysis of ER activation in breast cancer highlighted key components of the ER complex alongside a novel interaction with GRHL2. We demonstrate that GRHL2 is recruited to a subset of ER binding sites and regulates the transcriptional output of ER, as evidenced by changes in ER-associated eRNA expression, and stronger ER binding at active enhancers (H3K27ac sites) after GRHL2 knockdown.
Conclusions Our findings provide new insight into the role of GRHL2 in regulating eRNA transcription as part of ER signaling. These results demonstrate VULCAN, available from Bioconductor, as a powerful predictive tool.
Abbreviations
- AR
- Androgen Receptor
- ARACNe-AP
- AccuRate Algorithm for reConstruction of Network through Adaptive Partitioning
- CCLE
- Cancer Cell Line Encyclopedia
- ChIP
- Chromatin ImmunoPrecipitation
- E2
- Estradiol
- ER
- Estrogen Receptor-Alpha
- ERE
- Estrogen Response Elements
- eRNA
- Enhancer RNA
- 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