Quantitative profiling of drug-responsive regulatory activity at the human genome scale

Environmental stimuli commonly act via changes in gene regulation. Human-genome-scale assays to measure such responses are indirect or require knowledge of the transcription factors (TFs) involved. Here, we present the first use of genome-wide high-throughput reporter assays to measure environmentally-responsive regulatory element activity. We focused on responses to glucocorticoids (GCs), an important class of pharmaceuticals and a standard model for gene regulation. Our assay library contains >108 unique fragments and covers the human genome at >50x. Changes in regulatory element activity correlated with changes in gene expression, histone modifications and transcription factor occupancy. We also detected allele-specific environmental responses. Notably, the assays did not require knowledge of the TFs that mediate GC responses, thus can be used to agnostically quantify genomic responses to environmental signals for which the underlying mechanism remains unknown. 12 input STARR-seq input libraries and 25 STARR-seq output libraries (five replicates of five different durations of 100 nM dexamethasone exposure).