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• W2912296007 abstract "Background: Estrogen Receptor-alpha (ER) is the main driver of ~75% of all breast cancers. Upon stimulation, ER forms a complex on the chromatin at enhancers and promoters that leads to increased transcription of nearby genes. A critical feature of ER action is a cyclical binding pattern with a period of 90 minutes. However, analysis of ER binding dynamics has so far been restricted to the promoters of individual target genes. It is unknown how cyclical ER binding occurs genome-wide and whether this phenomenon is influenced by ER cofactors. Results: Here, we present a novel approach to dissect the regulation of ER activation based on network analysis of time-course genome-wide DNA binding data. We measured ER binding by ChIP-Seq at three timepoints (0, 45, 90 minutes) and developed an approach, called VULCAN, to overlay this binding information on a gene coexpression network. We benchmarked our approach in a comparison study and confirmed that it rediscovered known components of the ER signalling axis. Using VULCAN, we found that the activation ER results in the reprogramming of the transcription factor GRHL2 and independently validated this result by ChIP-seq and quantitative proteomics (qPLEX-RIME). Further, E2-responsive GRHL2 binding was found to be concurrent with an ER-responsive increase in eRNA transcription, and we show GRHL2 negatively regulates transcriptional activity at these sites.Conclusions: We present a general framework to predict key regulatory proteins from differential transcription factor binding data, which uncovered that activation of the ER leads to reprogramming of GRHL2." @default.
• W2912296007 created "2019-02-21" @default.
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• W2912296007 date "2018-02-16" @default.
• W2912296007 modified "2023-09-24" @default.
• W2912296007 title "Network Dynamics of ER-α activation reveals reprogramming of GRHL2" @default.
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