Abstract:
Transcription factors (TFs) exert their regulatory influence through the binding of enhancers, resulting in coordination of gene expression programs. Active enhancers are often characterized by the presence of short, unstable transcripts termed enhancer RNAs - eRNAs. While their function remains unclear, we demonstrate that eRNAs are a powerful readout of TF activity. We infer sites of eRNA origination across hundreds of publicly available nascent transcription datasets and show that eRNAs initiate from sites of TF binding. By quantifying the co-localization of TF-binding motifs and eRNA origins, we derive a simple statistic capable of inferring TF activity. In doing so, we uncover dozens of previously unexplored links between diverse stimuli and the TFs they affect. Our approach constitutes a fundamentally unique strategy for discovering links between TF activity and phenotypes.

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